ObjectiveThrough the conduct of an individual-based intervention study, the main purpose of this project was to build and evaluate the required infrastructure that may enable routine practice of precision cancer medicine in the public health services of Norway, including modelling of costs.MethodsAn eligible patient had end-stage metastatic disease from a solid tumour. Metastatic tissue was analysed by DNA sequencing, using a 50-gene panel and a study-generated pipeline for analysis of sequence data, supplemented with fluorescence in situ hybridisation to cover relevant biomarkers. Cost estimations compared best supportive care, biomarker-agnostic treatment with a molecularly targeted agent and biomarker-based treatment with such a drug. These included costs for medication, outpatient clinic visits, admission from adverse events and the biomarker-based procedures.ResultsThe diagnostic procedures, which comprised sampling of metastatic tissue, mutation analysis and data interpretation at the Molecular Tumor Board before integration with clinical data at the Clinical Tumor Board, were completed in median 18 (8-39) days for the 22 study patients. The 23 invasive procedures (12 from liver, 6 from lung, 5 from other sites) caused a single adverse event (pneumothorax). Per patient, 0–5 mutations were detected in metastatic tumours; however, no actionable target case was identified for the current single-agent therapy approach. Based on the cost modelling, the biomarker-based approach was 2.5-fold more costly than best supportive care and 2.5-fold less costly than the biomarker-agnostic option.ConclusionsThe first project phase established a comprehensive diagnostic infrastructure for precision cancer medicine, which enabled expedite and safe mutation profiling of metastatic tumours and data interpretation at multidisciplinary tumour boards for patients with end-stage cancer. Furthermore, it prepared for protocol amendments, recently approved by the designated authorities for the second study phase, allowing more comprehensive mutation analysis and opportunities to define therapy targets.

No abstract

Background: The first phase of the MetAction trial established the required diagnostic infrastructure, implemented security-approved systems for handling of sensitive information, educated the Trial Team within the context of tumor boards, and estimated costs of the initiative within public health services. The endeavor enabled expedited and safe mutation profiling of metastatic tumors in order to offer molecularly matched medication for end-stage cancer (Ree et al., ESMO Open 2017;2:e000158). The aim of the second trial phase was to investigate the utility of the MetAction pipeline in clinical practice. Procedures: An eligible patient with end-stage metastatic disease from any origin had been on the previous line of systemic therapy for 6 or more weeks with radiologic evaluation intervals of 6-12 weeks and disease progression according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Biopsy-sampled metastatic tissue was analyzed by DNA sequencing (Ion Oncomine™ Comprehensive Panel), where called variants were filtered prior to assessment and prioritization, supplemented with fluorescence in situ hybridization to cover relevant biomarkers. The Molecular Tumor Board interpreted the findings within the likelihood of signaling pathway activity, for the sequential Clinical Tumor Board to conclude on potential systemic tumor-directed medication. On study therapy, radiologic work-up was performed every 8 weeks. The primary objective was to compare progression-free survival (PFS) on study treatment, termed Period-B, with PFS for the most recent therapy, termed Period-A. If Period-B/Period-A was ≥1.3, the study therapy was deemed to be of benefit. The incidence of diagnostic adverse events and treatment-related grade 3-5 Common Terminology Criteria for Adverse Events (CTCAE) toxicities was secondary end points. Results: 26 patients were enrolled. Biopsy procedures were undertaken at lung or pleural sites (6 cases), liver or peritoneal sites (19 cases), and an inguinal lymph node (1 case), and did not cause adverse events. Histologic entities were 18 adenocarcinomas (AC), 2 undifferentiated carcinomas, 1 case each of cholangiocarcinoma and squamous cell carcinoma, and 4 different sarcoma entities. 13 patients were found eligible for off-label use of molecularly matched therapy (inhibitor of ALK-, BRAF-, EGFR-, FGFR-, mTOR-, PARP-, ROS1-, or PD-1-mediated signaling). Among the 10 individuals who received study treatment until radiologic evaluation, 5 met the primary end point. The patient with cholangiocarcinoma and a patient with rectal AC primaries, both given crizotinib, obtained Period-B/Period-A outcome slightly better than 1.3. Notably, 3 patients with colon AC primaries, receiving either a combination of panitumumab with vemurafenib or chemotherapy or single-agent pembrolizumab, obtained long-lasting responses. In addition, 1 colon AC patient receiving pembrolizumab with RECIST progression (i.e., primary end point failure) before a long-lasting response to off-protocol continuation, reported CTCAE grade 3 toxicity (a colitis event that immediately resolved on high-dose prednisolone). Conclusion: MetAction procedures and treatments were safe. 15% (4/26) of patients with progressing end-stage cancer had the disease course substantially reversed by this biomarker-directed therapy approach. Citation Format: Anne Hansen Ree, Kjersti Flatmark, Vigdis Nygaard, Daniel Heinrich, Kjetil Boye, Svein Dueland, Vegard Nygaard, Eivind Hovig, Klaus Beiske, Marius Lund-Iversen, Vivi A. Flørenes, Christin Johansen, Inger Riise Bergheim, Menaka Sathermugathevan, Sigve Nakken, Gry A. Geitvik, Ole C. Lingjærde, Anne-Lise Børresen-Dale, Hege G. Russnes, Gunhild M. Mælandsmo. The MetAction trial: long-lasting responses to molecularly matched therapy in end-stage cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A101.

e14033 Background: The MetAction project consists of two clinical trial phases. The completed first phase established the required diagnostic infrastructure, implemented security-approved systems for handling of sensitive information, educated the entire project staff within the context of tumor boards, and estimated costs of the initiative within public health services. The endeavor enabled expedite and safe mutation profiling of metastatic tumors in order to offer biomarker-based treatment with molecularly matched medication to patients with end-stage cancer, as reported in Ree et al., ESMO Open 2017. The ongoing second trial phase investigates the feasibility of the established MetAction pipeline in clinical practice. Methods: An eligible patient has end-stage metastatic disease from a solid cancer. Metastatic tissue is analyzed by DNA sequencing (Ion Oncomine™ Comprehensive Panel), where called variants are filtered prior to assessment and prioritization, supplemented with fluorescence in situ hybridization to cover relevant biomarkers. The Molecular Tumor Board interprets the findings within the likelihood of signaling pathway activity, and the sequential Clinical Tumor Board (CTB) may conclude on treatment with any systemic tumor-directed medication. Results: At the time of writing, 19 patients enrolled onto the second trial phase have accomplished the diagnostic procedures from sampling of metastatic tissue to CTB conclusion. Biopsy procedures were undertaken at lung or pleural sites (five cases), liver or superficial or deep peritoneal sites (13 cases), and an inguinal lymph node (one case) and did not cause adverse events. Histologic entities were 12 adenocarcinomas and one case each of squamous cell and undifferentiated carcinoma, cholangiocarcinoma, and four different sarcoma entities. Twelve patients have been found eligible for off-label use of molecularly matched therapy (inhibitor of ALK-, BRAF-, EGFR-, FGFR-, mTOR-, PARP-, or PD-1-mediated signaling). Conclusions: We will report on patient outcome (progression-free survival, overall response rate, and tolerance) to this biomarker-directed treatment in end-stage cancer. Clinical trial information: NCT02142036.