Patients with Rare Cancers in the Drug Rediscovery Protocol (DRUP) Benefit from Genomics-Guided Treatment

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 patients with rare cancer benefit from approved anticancer drugs outside their label similar to common cancers.

Experimental design: In the Drug Rediscovery Protocol (DRUP), patients with therapy-refractory metastatic cancers harboring an actionable molecular profile are matched to FDA/European Medicines Agency-approved targeted therapy or immunotherapy. Patients are enrolled in parallel cohorts based on the histologic tumor type, molecular profile and study drug. Primary endpoint is clinical benefit (complete response, partial response, stable disease ≥ 16 weeks).

Results: Of 1,145 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 nonrare cancer subgroup. Inactivating alterations of CDKN2A and activating BRAF aberrations were overrepresented in patients with rare cancer compared with nonrare cancers, resulting in more matches to CDK4/6 inhibitors (14% vs. 4%; P ≤ 0.001) or BRAF inhibitors (9% vs. 1%; P ≤ 0.001). Patients with rare cancer treated with small-molecule inhibitors targeting BRAF experienced higher rates of clinical benefit (75%) than the nonrare cancer subgroup.

Conclusions: Comprehensive molecular testing in patients with rare cancers may identify treatment opportunities and clinical benefit similar to patients with common cancers. Our findings highlight the importance of access to broad molecular diagnostics to ensure equal treatment opportunities for all patients with cancer.

Figure 1.

Flowchart of submitted and enrolled cases. SoC, standard-of-care treatments; VUS, variant of unknown significance.

Figure 2.

Molecular targets used for submission/enrollment. Representation of all genes harboring somatic alterations that were reviewed by the study team and enrolled in the trial of rare cancer (A) and nonrare cancer (B) patients. For enrolled patients, the target depicted was matched for treatment. None indicates that only the RAF/RAS wild-type status could confer anti-EGFR treatment (panitumumab) or that there was no actionable target present.

Figure 3.

Waterfall plot. Waterfall plots depicting best RECIST 1.1 response of rare cancer subgroup (A) and nonrare cancer subgroup (B). Colors denote the different treatment types, as defined in the legend.

Figure 4.

Clinical benefit. Boxplot showing clinical benefit (CB; yes or no) per drug type and involved pathway in absolute numbers (n; upper figure) and percentage (%; bottom figure) of rare cancers (A) and nonrare cancers (B). i, inhibitor; NE, not evaluable.

Figure 5.

Progression-free survival (A) and overall survival curves (B) (rare versus nonrare cancers).