Patterns of progression on first line osimertinib in patients with EGFR mutation-positive advanced non-small cell lung cancer (NSCLC): A Swiss cohort study.

AIM: Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) approved for patients with EGFR mutated non-small cell lung cancer as first-line treatment. However, treatment resistance inevitably emerges and may present as oligo-progressive disease (OPD) or systemic progressive disease (SPD). The incidence of OPD on first-line osimertinib is unknown. METHODS: We retrospectively analyzed patients who received first-line osimertinib at 13 Swiss centers. The rate of OPD (PD in ≤ 5 lesions) and treatment outcomes were analyzed. RESULTS: The median age of the 148 patients was 68.2 years (range. 38.0-93.3). There were 62 % females, 83 % with a PS ≤ 1, 59 % never smokers, 57 % of patients with an EGFR exon 19 deletion and 37 % with EGFR p.L858R exon 21. 77 % experienced OPD. Median overall survival (OS) was 51.6 months (95 % CI, 38.4-65.0). Median progression-free survival (PFS) was 19.2 (95 % CI, 14.3-23.5) and 8.7 (95 % CI, 2.8-15.6) months for patients with common and uncommon EGFR mutations. Patients with OPD compared to SPD had a significantly longer time to treatment failure and longer OS of (22.9 vs. 10.8 months, p < 0.001 and 51.6 vs. 26.4 months, p = 0.004, respectively). The most common organ sites of PD were lung (62 %), brain (30 %), lymph nodes (30 %), bone (27 %) and pleura (27 %). Twenty-six patients (45 %) with OPD received local ablative treatment (LAT). The OS of OPD patients with LAT was 60.0 (95 % CI, 51.6-NA) vs. 51.4 (95 % CI 38.4-65.3) months (p = 0.43) without LAT. CONCLUSION: The rate of OPD of patients receiving first line osimertinib was 77 %. Patients with OPD had a significantly better OS compared to patients with SPD (51.6 vs. 26.4 months). Patients with OPD receiving LAT had the longest median OS (60.0 months).

Patterns of progression on osimertinib in EGFR T790M positive NSCLC: A Swiss cohort study.

INTRODUCTION: Osimertinib is an EGFR tyrosine kinase inhibitor (TKI) with antitumor activity in non-small cell lung cancer (NSCLC) with EGFR T790 M mutations. The incidence of oligo-progression (PD) on osimertinib is unknown. METHODS: We retrospectively analyzed 50 pre-treated EGFR T790M-positive NSCLC patients treated with osimertinib at seven Swiss centers. Oligo-PD was defined as PD in ≤ 5 lesions. Mutational profiling of pre- and post-osimertinib tumor samples was performed. RESULTS: Median age was 62 years (37-89), 64% were females, 86% had a PS ≤ 1, 54%/13% were never/current smokers. Median follow-up was 15.3 (IQR: 8.6-21.6) months. Overall response rate was 80%, median progression-free survival 12.1 months (95% CI 8.3-18.3), median overall survival 28 months (95% CI 20.2-not reached [NR]) and median treatment duration 18.8 months (95%CI 16-8-NR). PD occurred in 36 patients (72%). 73% had oligo-PD. Median osimertinib treatment duration in patients with oligo-PD was 19.6 vs. 7 months if systemic PD (p = 0.007). The number of progressive lesions in patients with oligo-PD was 1 (27%), 2 (35%) and 3-5 (39%). Sites of PD included lungs (56%), bones (44%), and brain (17%). Sixteen patients with oligo-PD continued treatment with osimertinib for a median of 6.7 months beyond PD. Thirteen received local ablative treatment (LAT). In pre- and post-PD tumor tissue multiple molecular alterations were detected. CONCLUSION: In patients with acquired resistance to osimertinib, we observed a high rate (73%) of oligo-PD. Outcomes of patients receiving LAT were favorable, supporting the concept of osimertinib treatment beyond progression in combination with LAT of progressing lesions.

Malignant melanoma in patients with hereditary nonpolyposis colorectal cancer.

BACKGROUND: Malignant melanoma (MM) is the most aggressive skin cancer. Most MMs are sporadic, and in this setting an association with mismatch repair (MMR) gene mutations, typical of hereditary nonpolyposis colorectal cancer (HNPCC) tumours, has been proposed. OBJECTIVES: To characterize clinically and/or by molecular biology the patients with MM belonging to a cohort of 60 kindreds with HNPCC. Methods Patients with HNPCC with a diagnosis of MM were studied by immunohistochemistry (IHC) on tumour tissue using antibodies to MLH1, MSH2, p16, beta-catenin and E-cadherin, and by direct sequencing of MMR genes on germline DNA, and BRAF and NRAS on somatic DNA extracted from MM. RESULTS: Nine cutaneous MMs were detected in the tumour spectrum of eight families with HNPCC. The median age at diagnosis was 46 years. In one HNPCC family the diagnosis of MM was made in two first-degree relatives fitting the clinical definition of familial melanoma. IHC and sequencing analysis showed an MSH2 mutation in one patient with MM. CONCLUSIONS: Dermatological surveillance should be recommended to families in which MM is diagnosed in at least one member, especially at a young age. The combination of MMR gene mutations and abnormalities of p16 or other molecular pathways is needed to induce melanocytic carcinogenesis in a familial setting as well as in sporadic MM.

MicroRNAs in non-small cell lung cancer: current status and future therapeutic promises.

A biological characterization of tumor tissue is mandatory in NSCLC patients to identify cases at high risk of recurrence and to drive current targeted therapies such as EGFR and ALK inhibitors. In addition, promising results have been reported on the utility of molecular parameters for the prediction of the efficacy of systemic cytotoxic therapy. MicroRNAs (miRNAs) are small single stranded non-coding RNA molecules, which regulate gene expression at the posttranscriptional level. Growing evidence suggests that miRNAs are expressed aberrantly in many human cancers and that they play a significant role in carcinogenesis and cancer progression. There is increasing evidence that miRNA profiling may become an accurate way to differentiate tumor subtypes, determine prognosis and response to therapy. This review aims to summarize the current literature on this rapidly evolving field.

Feasibility and safety of autotransplants with noncryopreserved marrow or peripheral blood stem cells: a systematic review.

The objective of this systematic review is to examine the feasibility and safety of autologous noncryopreserved stem-cell transplants. This technique avoids the cost of establishing and maintaining a cryopreservation facility and may be of value for transplant centers in regions with limited economic resources. The primary outcome was the graft failure rate. In addition, a detailed description of the high-dose therapy regimens employed was undertaken. Secondary outcomes were transplant-related mortality and neutrophil and platelet engraftments times. Sixteen well-conducted nonrandomized studies met the eligibility criteria. Only two cases of graft failure (0.36%) occurred among 560 assessable patients receiving high-dose therapy and autotransplant for non-Hodgkin's lymphoma, Hodgkin's lymphoma, multiple myeloma, germ-cell tumors and acute leukemias. The most traditional high-dose schedules were used, although often modified to shorter regimens. High-dose melphalan appeared especially useful given its short half-life and was used to treat multiple myeloma by most groups. Secondary outcomes were comparable to those reported in the most relevant studies addressing standard (cryopreserved) autotransplant. According to this study, the use of autologous noncryopreserved hematopoietic progenitors to support patients undergoing high-dose therapy is feasible and safe.