Molecularly Targeted Treatment for Cancer of Unknown Primary

Cancer of unknown primary (CUP) has been associated with a poor prognosis, short survival, and treatment approaches that typically utilize generic chemotherapy regimens with antitumor activity in the most likely primary sites of disease. These regimens often are platinum- or taxane-based combinations associated with little improvement in overall survival (OS). To determine the effect of a molecularly guided treatment (MGT) of CUP, researchers conducted an industry-sponsored, multinational, phase 2, open-label trial.

They enrolled 636 patients with nonsquamous CUP and good functional status who were eligible for platinum-based chemotherapy and had tumor tissue or liquid biopsy material available for gene expression profiling. Patients first received three cycles of induction chemotherapy with a platinum-based regimen (carboplatin-paclitaxel, cisplatin-gemcitabine, or carboplatin-gemcitabine). Those with tumor response or stable disease (n=436) were then randomized to either MGT or continuation of the same chemotherapy. Patients randomized to the MGT group who did not have a targetable alteration, high tumor mutational burden, or high microsatellite instability were treated with chemotherapy plus atezolizumab.

Median follow-up was 24 months. Median progression-free survival (PFS) was 6.1 months in the MGT group and 4.4 months in the chemotherapy group, a significant difference (hazard ratio, 0.72; P=0.0079). Median OS was not significantly different between the groups (MGT, 14.7 months; continued chemotherapy, 11.0 months). Among the 88 patients with an actionable mutation receiving MGT, PFS was 8.1 months, versus 4.7 months for those receiving chemotherapy.