Patients With Rare Cancers in the Drug Rediscovery Protocol (DRUP) benefit from Genomics - Guided Treatment Genomics – Guided Treatment of Rare Cancer Patients in DRUP

as much as 24% of all diagnoses. However, these significant subgroup of cancer patients have significantly less access to new treatment opportunities and are understudied at the level of genomic targets compared to patients with common cancers. In the Drug Rediscovery Protocol (DRUP), patients with therapy refractory metastatic cancers, harboring an actionable molecular profile are matched to an available FDA/EMA approved targeted- or immunotherapy. Our study shows that there is a significant overlap in genomic targets between common and rare cancers. Also, progression free survival and overall survival for common cancers and rare cancers treated in DRUP were similar. Furthermore, exceptional responders have been observed in the rare care cancer group highlighting the importance that rare cancers deserve similar access to diagnostics and novel treatment approaches to avoid inequality in care. Abstract Purpose Patients with rare cancers (incidence less than 6 cases per 100,000 persons per year) commonly have less treatment opportunities and are understudied at the level of genomic targets. We hypothesized that rare cancer patients benefit from approved anti-cancer drugs outside their label similar to common cancers. In the Drug Rediscovery Protocol (DRUP), therapy refractory metastatic cancers patients, harboring an actionable molecular profile are matched to FDA/EMA approved targeted- or immunotherapy. Patients are enrolled in parallel cohorts based on the histological tumor type, molecular profile and study drug. Primary endpoint is clinical benefit (CR, PR, SD ≥ 16 weeks). Results Of 1145 submitted cases, 500 patients, including 164 patients with rare cancers started one of the 25 available drugs and were evaluable for treatment outcome. The overall clinical benefit rate was 33% in both the rare cancer and non-rare cancer subgroup. Inactivating alterations of CDKN2A and activating BRAF aberrations were overrepresented in rare cancer patients compared to non-rare cancers, resulting in more matches to CDK4/6 inhibitors (14% vs 4%; P = < 0.001) or BRAF inhibitors (9% vs. 1%; P = < 0.001). Rare cancer patients treated with small molecule inhibitors targeting BRAF , experienced higher rates of clinical benefit (75%) than the non-rare cancer subgroup.