Egfr inhibition in a pretreated sacral chordoma: a rolefor erlotinib? Case report and a brief review of literature

We describe the case of a 69-year old male with an EGFR- positive Imatinib refractory sacral chordoma with synchronous lung metastases, treated with erlotinib, a first- generation EGFR inhibitor. After disease progression following firstline Imatinib and a combination therapy with everolimus plus metformin, we made a challenge with an EGFR tyrosine kinase inhibitor (EGFR TKI), erlotinib. Despite a brief clinical benefit, the patient presented a rapid clinical deterioration leading to death, after 8 weeks of treatment

The accelerated path of ceritinib: Translating pre-clinical development into clinical efficacy

Abstract The discovery of anaplastic lymphoma kinase ( ALK )-rearranged non–small-cell lung cancer (NSCLC) in 2007 led to the development and subsequent approval of the ALK inhibitor crizotinib in 2011. However, despite its clinical efficacy, resistance to crizotinib invariably develops. There is now a next generation of ALK inhibitors, including two that have been approved—ceritinib and alectinib—and others that are in development—brigatinib, lorlatinib and X-396. Ceritinib and the other next-generation ALK inhibitors are more potent than crizotinib and can overcome tumor cell resistance mechanisms. Ceritinib gained US Food and Drug Administration approval in 2014 following accelerated review for the treatment of patients with ALK -positive ( ALK +) metastatic NSCLC who have progressed on or are intolerant to crizotinib. In pre-clinical studies, it demonstrated more potent inhibition of ALK than crizotinib in enzymatic assays, more durable responses in xenograft models and the ability to potently overcome crizotinib resistance mutations in vitro (including the gatekeeper mutation). There is also evidence for ceritinib penetration across the blood-brain barrier. In clinical trials, ceritinib has demonstrated durable responses and progression-free survival in ALK-inhibitor–pre-treated and –naive NSCLC patients, including high overall and intracranial response rates in those with central nervous system metastases. Selective gastrointestinal toxicity of ceritinib, such as diarrhea, nausea and vomiting is generally manageable with prophylactic medication and prompt dose reduction or interruption. Future progress in treating ALK + NSCLC will focus on determining the optimal sequencing of therapies and strategies to overcome acquired resistance, an ongoing challenge in treating ALK -mutation–driven tumors

EGFR-TKI plus anti-angiogenic drugs in EGFR-mutated NSCLC: a meta-analysis of randomized clinical trials

Abstract Background Results of several RCTs testing the combination of an EGFR-TKI plus an anti-angiogenic drug in advanced EGFR-mutated NSCLC were reported. Methods We first report a systematic-review and meta-analysis of all RCTs, to estimate effectiveness and toxicity of such new therapeutic approach as compared with first-generation EGFR-TKIs monotherapy. Subsequently, we present a network meta-analysis (NMA) comparing the combination of an EGFR-TKI plus an anti-angiogenic drug with other two new treatment-options: combination of an EGFR-TKI plus chemotherapy or new EGFR-TKIs of second or third generation as monotherapy. Results Five RCTs were included in the first meta-analysis. The PFS was statistically significantly larger in patients treated with an EGFR-TKI plus an anti-angiogenic drug as compared with EGFR-TKI monotherapy: the pooled PFS-HR was 0.59 (95% CI = 0.51 to 0.69). The pooled median-PFS was 17.8 months (95% CI = 16.5 to 19.3) for the combination versus 11.7 months (95% CI = 11.1 to 12.7) for EGFR-TKI as monotherapy. No statistically significant differences between the two treatment-arms were observed in terms of both OS and ORR. The rate of grade equal or higher than 3 AEs was statistically significantly higher in patients treated with EGFR-TKI plus an anti-angiogenic drug: the pooled-Relative Risk was 1.72 (95% CI = 1.43 to 2.06). Ten RCTs were included in the NMA. All the three experimental treatments were associated with a statistically significant improvement of PFS as compared with first-generation EGFR-TKIs. When compared to each other, none of the three experimental treatments was statistically significantly associated with larger PFS or lower rate of grade ≥3AEs. Conclusion Patients with EGFR-mutated NSCLC derived clinically meaningful larger PFS-benefit from the addition of an anti-angiogenic drug to a first-generation EGFR-TKI, at the cost of an increase of toxicitie

Safety and Immunogenicity of MAGE-A3 Cancer Immunotherapeutic with or without Adjuvant Chemotherapy in Patients with Resected Stage IB to III MAGE-A3-Positive Non-Small-Cell Lung Cancer

Introduction: To assess the safety and immunogenicity of MAGE-A3 immunotherapeutic in patients with stage IB-III MAGE-A3-positive non-small-cell lung cancer (NSCLC) who were or were not undergoing standard cisplatin/vinorelbine chemotherapy. Methods: This open, prospective, multicenter, parallel-group phase I study (NCT00455572) enrolled patients with resected (cohorts 1-3) or unresectable (cohort 4) MAGE-A3-positive NSCLC. MAGE-A3 immunotherapeutic (300 g recombinant MAGE-A3 formulated with AS15) was administered (eight doses, 3 weeks apart) concurrent with (cohort 1), after (cohort 2), or without (cohort 3) standard-adjuvant chemotherapy, or after standard radiotherapy and/or chemotherapy (cohort 4). Results: Sixty-seven patients received greater than or equal to 1 dose of MAGE-A3 immunotherapeutic. Grade 3/4 adverse events (AEs) were reported for 16 out of 19 (84%), 2 out of 18 (11%), 5 out of 18 (28%), and 1 out of 12 (8%) patients in cohorts 1, 2, 3, and 4, respectively. Many grade 3/4 AEs in cohort 1 (e.g., neutropenia) were typical of chemotherapy. Six patients, including three in cohort 1, reported study treatment-related grade 3/4 AEs (injection-site reactions or musculoskeletal/back pain, which resolved within 5 days). One patient (in cohort 4) died, but this and the other serious adverse events were not study treatment related. MAGE-A3-specific antibody responses to immunotherapy were induced in all patients evaluated in all cohorts. MAGE-A3-specific CD4(+) T-cell responses to immunotherapy were detected in 4 out of 11 (36%), 4 out of 15 (27%), 2 out of 8 (25%), and 5 out of 6 (83%) evaluated patients in cohorts 1, 2, 3, and 4, respectively; and CD8(+) T-cell responses were only detected in four patients. Conclusion: In resected and unresectable NSCLC patients and irrespective of whether standard chemotherapy was concurrent or not, MAGE-A3 immunotherapeutic is well tolerated and induces MAGE-A3-specific immune responses. GlaxoSmithKline Biologicals SA sponsored the clinical trial and covered the costs associated with the development and publishing of the manuscript, including scientific writing assistance. adjuvant chemotherapy; immunotherapy; immunostimulant; MAGE-A3; non–small cell lung carcinoma; vaccin

Early Prediction of Response to Tyrosine Kinase Inhibitors by Quantification of EGFR Mutations in Plasma of NSCLC Patients.

IntroductionThe potential to accurately quantify epidermal growth factor receptor (EGFR) mutations in plasma from non–small-cell lung cancer patients would enable more rapid and more frequent analyses to assess disease status; however, the utility of such analyses for clinical purposes has only recently started to explore.MethodsPlasma samples were obtained from 69 patients with EGFR-mutated tumors and 21 negative control cases. EGFR mutations in plasma were analyzed by a standardized allele-specific polymerase chain reaction (PCR) test and ultra-deep next-generation sequencing (NGS). A semiquantitative index (SQI) was derived from dilutions of known EGFR mutation copy numbers. Clinical responses were evaluated by Response Evaluation Criteria in Solid Tumors 1.1 criteria and expressed as percent tumor shrinkage.ResultsThe sensitivity and specificity of the PCR test and NGS assay in plasma versus tissue were 72% versus 100% and 74% versus 100%, respectively. Quantitative indices by the PCR test and NGS were significantly correlated (p < 0.001). EGFR testing at baseline and serially at 4 to 60 days during tyrosine kinase inhibitor therapy revealed a progressive decrease in SQI, starting from day 4, in 95% of cases. The rate of SQI decrease correlated with percent tumor shrinkage at 2 months (p < 0.0001); at 14 days, it was more than 50% in 70% of patients (rapid responders). In two patients with slow response, an early increase in the circulating levels of the T790M mutation was observed. No early T790M mutations were seen in plasma samples of rapid responders.ConclusionsQuantification of EGFR mutations from plasma with a standardized PCR test is feasible. To our knowledge, this is the first study showing a strong correlation between the EGFR SQI in the first days of treatment and clinical response with relevant implications for patient management

Safety and Immunogenicity of the PRAME Cancer Immunotherapeutic in Patients with Resected Non–Small Cell Lung Cancer: A Phase I Dose Escalation Study

International audience; INTRODUCTION:Adjuvant platinum-based chemotherapy is standard treatment for surgically resected stage II to IIIA NSCLC, but the relapse rate is high. The preferentially expressed antigen of melanoma (PRAME) tumor antigen is expressed in two-thirds of NSCLC and offers an attractive target for antigen-specific immunization. A phase I dose escalation study assessed the safety and immunogenicity of a PRAME immunotherapeutic consisting of recombinant PRAME plus proprietary immunostimulant AS15 in patients with surgically resected NSCLC (NCT01159964).METHODS:Patients with PRAME-positive resected stage IB to IIIA NSCLC were enrolled in three consecutive cohorts to receive up to 13 injections of PRAME immunotherapeutic (recombinant PRAME protein dose of 20 μg, 100 μg, or 500 μg, with a fixed dose of AS15). Adverse events, predefined dose-limiting toxicity, and the anti-PRAME humoral response (measured by enzyme-linked immunosorbent assay) were coprimary end points. Anti-PRAME cellular responses were assessed.RESULTS:A total of 60 patients were treated (18 received 20 μg of PRAME, 18 received 100 μg of PRAME, and 24 received 500 μg of PRAME). No dose-limiting toxicity was reported. Adverse events considered by the investigator to be causally related to treatment were grade 1 or 2, and most were injection site reactions or fever. All patients had detectable anti-PRAME antibodies after four immunizations. The percentages of patients with PRAME-specific CD4-positive T cells were higher at the dose of 500 μg compared with lower doses. No predefined CD8-positive T-cell responses were detected.CONCLUSION:The PRAME immunotherapeutic had an acceptable safety profile. All patients had anti-PRAME humoral responses that were not dose related, and 80% of those treated at the highest dose showed a cellular immune response. The dose of 500 μg was selected. However, further development was stopped after negative results with a similar immunotherapeutic in patients with NSCLC

Guideline-Based Follow-Up Outcomes in Patients With Gastrointestinal Stromal Tumor With Low Risk of Recurrence: A Report From the Italian Sarcoma Group

Importance: Gastrointestinal stromal tumor (GIST) follow-up is recommended by international guidelines, but data on the role of follow-up in patients with low relapse risk are missing. For these patients, the potential benefit of anticipating recurrence detection should be weighed against psychological burden and radiologic examination loads in terms of costs and radiation exposure. Objective: To evaluate the outcomes of guideline-based follow-up in low-risk GIST. Design, setting, and participants: This multi-institutional retrospective cohort study involving Italian Sarcoma Group reference institutions evaluated patients with GIST who underwent surgery between January 2001 and June 2019. Median follow-up time was 69.2 months. Data analysis was performed from December 15, 2022, to March 20, 2023. Patients with GIST at low risk according to Armed Forces Institute of Pathology criteria were included provided adequate clinical information was available: primary site, size, mitotic index, surgical margins, and 2 or more years of follow-up. Exposures: All patients underwent follow-up according to European Society for Medical Oncology (ESMO) guidelines. Main outcomes and measures: The primary outcome was the number of tests needed to identify a relapse according to ESMO guidelines follow-up plan. Secondary outcomes included relapse rate, relapse timing, disease-free survival (DFS), overall survival (OS), GIST-specific survival (GIST-SS), postrelapse OS, secondary tumor rates, and theoretical ionizing radiation exposure. An exploratory end point, new follow-up schedule proposal for patients with low-risk GIST according to the observed results, was also assessed. Results: A total of 737 patients (377 men [51.2%]; median age at diagnosis, 63 [range, 18-86] years) with low-risk GIST were included. Estimated 5-year survival rates were 95.5% for DFS, 99.8% for GIST-SS, and 96.1% for OS. Estimated 10-year survival rates were 93.4% for DFS, 98.1% for GIST-SS, and 91.0% for OS. Forty-two patients (5.7%) experienced disease relapse during follow-up (9 local, 31 distant, 2 both), of which 9 were detected after 10 or more years. This translated into approximately 1 relapse detected for every 170 computed tomography scans performed, with a median radiation exposure of 80 (IQR, 32-112) mSv per patient. Nongastric primary tumor (hazard ratio [HR], 2.09; 95% CI, 1.14-3.83; P = .02), and KIT mutation (HR, 2.77; 95% CI, 1.05-7.27; P = .04) were associated with a higher risk of relapse. Second tumors affected 187 of 737 patients (25%), of which 56 were detected during follow-up and represented the primary cause of death in these patients. Conclusions and relevance: In this cohort study on patients affected by low-risk GISTs, the risk of relapse was low despite a follow-up across 10 or more years. These data suggest the need to revise follow-up schedules to reduce the anxiety, costs, and radiation exposure of currently recommended follow-up strategy

Final results of the large-scale multinational trial PROFILE 1005: efficacy and safety of crizotinib in previously treated patients with advanced/metastatic ALK-positive non-small-cell lung cancer

Purpose Crizotinib is a potent, orally administered tyrosine kinase inhibitor approved for the treatment of anaplastic lymphoma kinase (ALK)-positive advanced non-small-cell lung cancer (NSCLC). We report final results from PROFILE 1005, the largest clinical trial to date for an ALK inhibitor in ALK-positive NSCLC. Patients and methods PROFILE 1005 (NCT00932451) was a multicenter, single-arm phase 2 trial of the efficacy, safety and tolerability of crizotinib (250 mg twice daily; 3 week continuous treatment cycles) in patients with ALK-positive NSCLC after failure of ≥1 lines of systemic treatment for locally advanced/metastatic disease. Patients’ tumour ALK status was initially determined by a central laboratory until a protocol amendment permitted enrolment of patients based on locally determined ALK status. Co-primary endpoints were objective response rate (ORR), evaluated using Response Evaluation Criteria in Solid Tumours V.1.1 and adverse events (AEs). Cancer-specific patient-reported outcomes (PROs) were also assessed using the European Organisation for the Research and Treatment of Cancer QLQ-C30 and its lung cancer module QLQ-LC13. Results: 1069 patients were enrolled; 1066 received crizotinib. The as-treated population comprised 908 and 158 patients, in whom tumour positive ALK-status was determined centrally (± locally) or locally only, respectively. At baseline, a majority of patients were <65 years (84%), 66% were never smokers and 46% were Asian. Derived investigator-assessed ORR was 54% (95% CI 51 to 57) and 41% (95% CI 33 to 49) in the central-testing and local-testing subgroups, respectively. The most common treatment-related AEs in the overall population (any grade) were vision disorder (58%), nausea (51%), diarrhoea (47%) and vomiting (47%). PRO scores demonstrated clinically meaningful improvement in lung cancer symptoms and global quality of life. Conclusion: The efficacy, safety and PRO profiles of crizotinib in this cohort of 1066 patients with ALK-positive NSCLC are consistent with previous reports. Trial registration number Phase 2 trial (NCT00932451); Results

Adjuvant Imatinib in Patients with GIST Harboring Exon 9 KIT Mutations : Results from a Multi-institutional European Retrospective Study

Purpose: The effect of high-dose imatinib (800 mg/day) on survival in the adjuvant treatment of patients with resected KIT exon 9-mutated gastrointestinal stromal tumors (GIST) is not established. Here, the association of dose and other clinicopatho-logic variables with survival was evaluated in a large multi-institutional European cohort. Experimental Design: Data from 185 patients were retrospec-tively collected in 23 European GIST reference centers. Propen-sity score matching (PSM) and inverse-probability of treatment weighting (IPTW) were used to account for confounders. Uni-variate and multivariate unweighted and weighted Cox propor-tional hazard regression models were estimated for relapse-free survival (RFS), modified-RFS (mRFS) and imatinib failure-free survival (IFFS). Univariate Cox models were estimated for overall survival. Results: Of the 185 patients, 131 (70.8%) received a starting dose of 400 mg/d and the remaining 54 (29.2%) a dose of 800 mg/d. Baseline characteristics were partially unbalanced, suggesting a potential selection bias. PSM and IPTW analyses showed no advantage of imatinib 800 mg/d. In the weighted multivariate Cox models, high-dose imatinib was not associated with the survival outcomes [RFS: hazard ratio (HR), 1.24; 95% confidence interval (CI), 0.79-1.94; mRFS: HR, 1.69; 95% CI, 0.92-3.10; IFFS: HR, 1.35; 95% CI, 0.79- 2.28]. The variables consistently associated with worse survival out-comes were high mitotic index and nongastric tumor location. Conclusions: In this retrospective series of patients with KIT exon 9-mutated GIST treated with adjuvant imatinib, a daily dose of 800 mg versus 400 mg did not show better results in terms of survival outcomes. Prospective evaluation of the more appropriate adjuvant treatment in this setting is warranted.Peer reviewe