Sigbjørn Smeland

Background and purpose: Molecular profiling guides cancer treatment, by identifying actionable genomic alterations. The IMPRESS-Norway trial (NCT04817956) is a nation-wide precision medicine trial evaluating the efficacy of approved cancer drugs on a novel indication in patients with advanced cancers harbouring potentially actionable alterations. Trametinib, a selective MEK1/2 inhibitor targeting the Mitogen-Activated Protein Kinase (MAPK) signalling pathway, is approved for BRAF V600 mutant melanoma but may also show activity in tumours with other alterations. This sub-study aimed to assess the efficacy of trametinib monotherapy across tumour types with alterations activating the MAPK signalling pathway.Patient/material and methods: In the IMPRESS-Norway trial patients are screened with the TruSight Oncology 500 panel or circulating tumour DNA profiling. Eligible patients are offered biomarker matched targeted therapies. In this subgroup analysis, we identified patients treated with trametinib monotherapy. Primary endpoints were disease control rate (DCR) after 16 weeks and safety. Secondary endpoints included progression-free survival (PFS) and overall survival (OS).Results: DCR after 16 weeks of treatment was 39% in 52 response evaluable patients, with four patients (8%) experiencing partial response, and 16 (31%) stable disease. Responses were seen in tumours harbouring BRAF fusions, GNA11, GNAQ, KRAS, NF1, and NRAS alterations, most frequently in low-grade serous ovarian cancer, central nervous system tumours, and uveal melanoma. Forty-eight percent of patients experienced treatment-related adverse events, including two treatment related deaths. Median PFS and OS were 4 and 9 months, respectively. Interpretation: Trametinib monotherapy achieved a 39% DCR in patients lacking standard options, supporting further studies to confirm efficacy and identify predictive biomarkers for treatment response.

Background and purpose: In Norway, comprehensive molecular tumour profiling is implemented as part of the public healthcare system. A substantial number of tumours harbour potentially targetable molecular alterations. Therapy outcomes may improve if targeted treatments are matched with actionable genomic alterations. In the IMPRESS-Norway trial (NCT04817956), patients are treated with drugs outside the labelled indication based on their tumours molecular profile. Patients and methods: IMPRESS-Norway is a national, prospective, non-randomised, precision cancer medicine trial, offering treatment to patients with advanced-stage disease, progressing on standard treatment. Comprehensive next-generation sequencing, TruSight Oncology 500, is used for screening. Patients with tumours harbouring molecular alterations with matched targeted therapies available in IMPRESS-Norway, are offered treatment. Currently, 24 drugs are available in the study. Primary study endpoints are percentage of patients offered treatment in the trial, and disease control rate (DCR) defined as complete or partial response or stable disease in evaluable patients at 16 weeks (W16) of treatment. Secondary endpoint presented is DCR in all treated patients. Results: Between April 2021 and October 2023, 1,167 patients were screened, and an actionable mutation with matching drug was identified for 358 patients. By the data cut off 186 patients have initiated treatment, 170 had a minimum follow-up time of 16 weeks, and 145 also had evaluable disease. In patients with evaluable disease, the DCR was 40% (58/145). Secondary endpoint analysis of DCR in all treated patients, showed DCR of 34% (58/170). Interpretation: Precision cancer medicine demonstrates encouraging clinical effect in a subset of patients included in the IMPRESS-Norway trial.

Integrated care pathway (ICP) is a prevailing concept in health care management including cancer care. Though substantial research has been conducted on ICPs knowledge is still deficient explaining how characteristics of diagnose, applied procedures, patient group and organizational context influence specific practicing of ICPs. We studied how coordination takes place in three cancer pathways in four Norwegian hospitals. We identified how core contextual variables of cancer pathways affect complexity and predictability of the performance of each pathway. Thus, we also point at differences in core preconditions for accomplishing coordination of the cancer pathways. In addition, the findings show that three different types of coordination dynamics are present in all three pathways to a divergent degree: programmed chains, consultative hubs and problem-solving webs. Pathway coordination also depends on hierarchical interaction. Lack of corresponding roles in the medical–professional and the administrative–institutional logics presents a challenge for coordination, both within and between hospitals. We recommend that further improvement of specific ICPs by paying attention to what should be standardized and what should be kept flexible, aligning semi-formal and formal structures to pathway processes and identify the professional cancer related background and management style required by the key-roles in pathway management.

The goal of coordinating pathways for cancer patients through their diagnostic and treatment journey is often approached by borrowing strategies from traditional industries, including standardization, process redesign, and variation reduction. However, the usefulness of these strategies is sometimes limited in the face of the complexity and uncertainty that characterize these processes over time and the situation at both patient and institutional levels. We found this to be the case when we did an in-depth qualitative study of coordination processes in patient pathways for three diagnoses in four Norwegian hospitals. What allows these hospitals to accomplish coordination is supplementing standardization with improvisation. This improvisation is embedded in four types of emerging semi-formal structures: collegial communities, networks, boundary spanners, and physical proximity. The hierarchical higher administrative levels appear to have a limited ability to manage and support coordination of these emerging structures when needed. We claim that this can be explained by viewing line management as representative of an economic–administrative institutional logic while these emerging structures represent a medical–professional logic that privileges proximity to the variation and complexity in the situations. The challenge is then to find a way for emergent and formal structures to coexist.