A phase 2 trial combining afatinib with cetuximab in patients with EGFR exon 20 insertion-positive non-small cell lung cancer.

BACKGROUND: Epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations are the third most common EGFR mutations in patients with non-small cell lung cancer (NSCLC) and are associated with primary resistance to EGFR tyrosine kinase inhibitors (TKIs). There is evidence of activity of combining EGFR TKIs with monoclonal antibodies. This study reports on the efficacy and safety of afatinib in combination with cetuximab. METHODS: In this single-arm phase 2 trial, patients with advanced NSCLC harboring an EGFR ex20ins mutation were treated with afatinib 40 mg once daily in combination with cetuximab 500 mg/m2 every 2 weeks. The primary end point was disease control rate (DCR) at 18 weeks of treatment. RESULTS: Thirty-seven patients started treatment, with a median age of 65 years (range, 40-80 years), 78% female, and 95% White. The study achieved its primary end point with a DCR of 54% at 18 weeks, an overall response rate (ORR) of 43%, and a 32% confirmed ORR. Best responses were partial (n = 16), stable (n = 16), progressive disease (n = 2), or not evaluable (n = 3). Median progression-free survival was 5.5 months (95% CI, 3.7-8.3 months) and median overall survival was 16.8 months (95% CI, 10.7-25.8 months). The most common treatment-related adverse events (TRAEs) were diarrhea (70%), rash (65%), dry skin (59%), paronychia (54%), and erythema (43%). Grade 3 TRAEs were reported in 54% of all patients. CONCLUSIONS: Combination treatment with afatinib and cetuximab demonstrated antitumor activity with a DCR of 54% at 18 weeks and a 32% confirmed ORR. Toxicity was significant, although manageable, after dose reduction.

A comprehensive overview of the heterogeneity of EGFR exon 20 variants in NSCLC and (pre)clinical activity to currently available treatments.

Activating EGFR mutations are commonly observed in non-small cell lung cancer (NSCLC). About 4-10 % of all activating epidermal growth factor receptor (EGFR) mutations are heterogenous in-frame deletion and/or insertion mutations clustering within exon 20 (EGFRex20+). NSCLC patients with EGFRex20+ mutations are treated as a single disease entity, irrespective of the type and location of the mutation. Here, we provide a comprehensive assessment of the literature reporting both in vitro and clinical drug sensitivity across different EGFRex20+ mutations. The activating A763_Y764insFQEA mutation has a better tumor response in comparison with mutations in the near- and far regions directly following the C-helix and should therefore be treated differently. For other EGFRex20+ mutations marked differences in treatment responses have been reported indicating the need for a classification beyond the exon-based classification. A further classification can be achieved using a structure-function modeling approach and experimental data using patient-derived cell lines. The detailed overview of TKI responses for each EGFRex20+ mutation can assist treating physicians to select the most optimal drug for individual NSCLC patients.

Exposure-Response Analysis of Osimertinib in EGFR Mutation Positive Non-Small Cell Lung Cancer Patients in a Real-Life Setting.

BACKGROUND: Osimertinib, an irreversible inhibitor of the epidermal growth factor receptor (EGFR) is an important drug in the treatment of EGFR-mutation positive non-small cell lung cancer (NSCLC). Clinical trials with osimertinib could not demonstrate an exposure-efficacy relationship, while a relationship between exposure and toxicity has been found. In this study, we report the exposure-response relationships of osimertinib in a real-life setting. METHODS: A retrospective observational cohort study was performed, including patients receiving 40 - 80 mg osimertinib as ≥ 2 line therapy and from whom pharmacokinetic samples were collected during routine care. Trough plasma concentrations (Cmin,pred) were estimated and used as a measure of osimertinib exposure. A previously defined exploratory pharmacokinetic threshold of 166 µg/L was taken to explore the exposure-efficacy relationship. RESULTS: A total of 145 patients and 513 osimertinib plasma concentration samples were included. Median progression free survival (PFS) was 13.3 (95% confidence interval (CI):10.3 - 19.1) months and 9.3 (95% CI: 7.2 - 11.1) months for patients with Cmin,pred < 166 µg/L and Cmin,pred ≥ 166 µg/L, respectively (p = 0.03). In the multivariate analysis, a Cmin,pred < 166 µg/L resulted in a non-statistically significant hazard ratio of 1.10 (95% CI: 0.60 - 2.01; p = 77). Presence of a EGFR driver-mutation other than the exon 19 del or L858R mutations, led to a shorter PFS with a hazard ratio of 2.89 (95% CI: 1.18 - 7.08; p = 0.02). No relationship between exposure and toxicity was observed (p = 0.91). CONCLUSION: In our real-life cohort, no exposure-response relationship was observed for osimertinib in the current dosing scheme. The feasibility of a standard lower fixed dosing of osimertinib in clinical practice should be studied prospectively.

Pharmacotherapy for treatment of lung cancer in the elderly.

INTRODUCTION: The chance for elderly patients with NSCLC to receive chemotherapy decreases significantly with age. In addition, older patients are often underrepresented in clinical trials. Consequently, due to the paucity of data, evidence-based decisions with regard to chemotherapy treatment strategies in the elderly are lacking. AREAS COVERED: We performed a literature search to identify mainly randomized trials focusing on treatment of NSCLC in older patients with chemotherapy and targeted therapy, toxicity and quality of life. In conclusion, the efficacy of regular chemotherapy and targeted therapy seems quite similar in older patients compared to their younger counterparts, with increased toxicity, but acceptable. However, these data are mostly derived from subgroup analyses and highly selected fit patients, which may not represent the general older population. EXPERT OPINION: Further research is necessary to investigate the role of a comprehensive geriatric assessment in older patients, before the start of a chemotherapeutic treatment. Proteomic tests can have potential in the future, if these tests turn out to be able to separate patients with advanced NSCLC into groups with better or worse outcomes. It can be of special interest for the elderly population, to prevent unnecessary side effects of a possible inferior treatment.

Quantification of extraprostatic extension in prostate cancer: different parameters correlated to biochemical recurrence after radical prostatectomy.

AIMS: Different methods to substage extraprostatic extension (EPE) were correlated with biochemical recurrence (BCR) after radical prostatectomy (RP). METHODS AND RESULTS: A total of 157 consecutive RP specimens with EPE were completely embedded. Twenty-three patients with adjuvant therapy or detectable postoperative PSA levels were excluded, leaving 134 patients for BCR analysis. Data were analysed using Kaplan-Meier survival and Cox regression analyses. In univariate analysis, maximal radial distance (RD) was associated with BCR as continuous (P = 0.006) and dichotomous (P = 0.002) parameters. In multivariate analysis, independent predictors of BCR were preoperative prostate-specific antigen (PSA) (P = 0.006), Gleason score (P = 0.001), positive surgical margins (P = 0.005), maximal RD dichotomized at 0.6 mm [= one high-power field (HPF)]; hazard ratio (HR) 3.4; 95% confidence interval (CI) 1.48-7.85; P = 0.004), total RD (P = 0.009) and EPE quantification according to Epstein (P = 0.002) and to Wheeler (P = 0.004). The 5-year risk of BCR was 20% (95% CI 0.65-0.94) in patients with RD ≤ 0.6 mm and 47% (95% CI: 0.41-0.65) with RD > 0.6 mm. The restriction of focal EPE in no more than two slides (Epstein and Wheeler) gave no better results. CONCLUSIONS: Maximal RD dichotomized at one HPF is an objective method to subdivide EPE and a strong, independent predictor for BCR after RP. Its use is recommended for substaging pT3a in future TNM classifications.