Molecularly Tailored Therapy in Advanced Pancreatic Cancer

TAILOR‐PANC (DPCG‐02) is an investigator‐initiated, multicenter, randomized phase 2 trialevaluating whether molecularly tailored second‐line therapy improves outcomes comparedwith standard‐of‐care treatment in patients with advanced pancreatic cancer.Although most pancreatic cancers harbor KRAS mutations, a smaller proportion containpotentially actionable molecular alterations, including selected mutations, gene fusions,amplifications, or biomarkers such as mismatch repair deficiency. Some of thesealterations can be targeted by medicines that are already available in Denmark, althoughthe medicines may have been developed or approved primarily for other cancer types.Observational studies suggest that patients with pancreatic cancer who receive treatmentmatched to an actionable alteration may have better outcomes than patients who receivenon‐matched treatment. However, this strategy has not been adequately evaluated in arandomized setting.Molecular profiling is performed before study allocation using tumor tissue and/or blood.Whole‐genome sequencing is preferred, but targeted next‐generation sequencing orwhole‐exome sequencing may be used when whole‐genome sequencing is unavailable. Theresults are summarized in a personalized molecular report. A national multidisciplinarymolecular tumor board, including pancreatic cancer oncologists, molecular biologists,pathologists, and computational biologists, reviews the molecular findings and assesseswhether an alteration is clinically actionable. A molecular alteration is consideredactionable when it can be matched to a specific anticancer treatment supported byclinical evidence and the treatment is available and reimbursed in Denmark.Participants whose cancers harbor an actionable, reimbursed molecular alteration arerandomized in a 1:1 ratio to:Arm 1: molecularly tailored therapy selected according to the recommendation of thenational molecular tumor board; or Arm 2: standard second‐line therapy according toDanish clinical guidelines.Because the molecular alteration determines the matched treatment, participants assignedto Arm 1 may receive different targeted treatments. The relevant drug‐specificrequirements, safety monitoring, dose modifications, and discontinuation criteria willapply to each treatment.Participants whose cancers do not harbor an actionable, reimbursed molecular alterationare assigned to Arm 3, a non‐randomized observational cohort receiving standard‐of‐caretherapy according to Danish guidelines. Data from this cohort will support exploratorycomparisons and provide information about outcomes among genomically profiled patientswithout an available matched treatment. Comparisons involving Arm 3 will be interpretedas non‐randomized because molecular characteristics and other prognostic factors maydiffer between the groups.The primary randomized comparison is progression‐free survival between Arms 1 and 2.Approximately 68 participants with actionable alterations are required for randomization,with approximately 65 progression‐free survival events planned for the primary analysis.The study is designed to provide approximately 80% power at a two‐sided significancelevel of 0.05 to detect a hazard ratio of 0.50. This corresponds to the design assumptionof an increase in median progression‐free survival from 3 months with standard therapy to6 months with molecularly tailored therapy. These values are statistical assumptions anddo not represent guaranteed treatment outcomes.Because actionable alterations are expected in only approximately 5%‐10% of patients withpancreatic cancer, up to 1,200 genomically profiled participants may be enrolled toidentify the required number for the randomized comparison. Recruitment is expected totake approximately 4 years, with approximately 1 additional year of minimum follow‐up forthe primary analysis.The study will also characterize overall survival, tumor response, duration of response,safety, and patient‐reported quality of life. Optional translational research will beconducted through the BIOPAC project under separate consent. Blood and available tumorsamples may be used to explore molecular and circulating biomarkers associated withtreatment response, resistance, and toxicity. Clinical and genomic data may also be usedin exploratory artificial intelligence and machine‐learning analyses intended to developpredictive models and identify potential therapeutic targets. These biomarker andcomputational analyses are exploratory and are not used as validated clinical testswithin this study.