Molecularly guided therapy improves survival outcomes for patients with a cancer of unknown primary

Patients with a newly diagnosed unfavorable cancer of unknown primary (CUP) treated with molecularly guided therapy (MGT) had significantly improved progression-free survival (PFS) compared to those treated with standard platinum-based chemotherapy, according to the results of an open-label, randomized, phase 2 study published in The Lancet.¹

Specifically, patients treated with MGT who had a molecular alteration that could be targeted with a drug available in the trial had a 28% reduced risk of disease progression compared to those treated with standard platinum-based chemotherapy (hazard ratio, 0.72 [95% CI, 0.56–0.92]; p = .0079). At a median follow-up of 24 months, PFS was 8.1 and 4.7 months, respectively, for patients with an actionable target. Improved overall survival also was noted, although the data are not yet mature enough for a final statistical analysis.

In the multinational trial known as CUPISCO, 436 patients with a newly diagnosed unfavorable nonsquamous CUP who had disease control after three cycles of induction chemotherapy were randomized to MGT (n = 326) or chemotherapy (n = 110). All patients underwent tissue- and/or liquid biopsy (blood)–based comprehensive genomic profiling (CGP) testing, depending on the availability of tumor tissue.

The results are the first randomized evidence showing the superiority of MGT over standard chemotherapy in patients with a newly diagnosed unfavorable CUP, according to the lead author of the study, Alwin Krämer, MD, head of the Clinical Cooperation Unit Molecular Hematology/Oncology of the German Cancer Research Center and the Department of Internal Medicine V of the University of Heidelberg.

A central aim of the trial was to establish proof of concept that including early CGP at the initial diagnostic workup would lead to improved outcomes over standard of care by offering patients more relevant treatment options via MGT.

“All patients with newly diagnosed unfavorable CUP should receive CGP at initial diagnosis, and those patients with a molecular target, including immunotherapy for patients with high tumor mutational burden, should receive MGT in the second-line at the latest,” says Dr Krämer, adding that one of the successful MGT options in the trial was immunotherapy with atezolizumab only in patients with a high tumor mutation burden.

Commenting on the study, Cathy Eng, MD, the David H. Johnson Endowed Chair in Surgical and Medical Oncology at the Vanderbilt–Ingram Cancer Center, agrees that CGP testing potentially could improve outcomes for patients with a CUP. She encourages oncologists to get CGP testing, if available, for their patients. “Given the limited expertise in CUP, the consideration of CGP can help guide a healthcare provider about better potential options, especially given the overall poor prognosis of these patients,” she says. However, she adds that access is still an issue because CGP is not a standard of care globally.