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Patients with unfavorable cancer of unknown primary (CUP) lived significantly longer without disease progression when they received molecularly guided therapy (MGT) instead of chemotherapy, according to a randomized trial.

Median progression-free survival (PFS) improved from 4.4 months to 6.1 months with treatment selected on the basis of comprehensive genomic profiling (CGP). In the subgroup of patients with an actionable molecular target, median PFS was 8.1 months with MGT and 4.7 months in patients who did not receive MGT. An interim analysis of overall survival (OS) showed a trend in favor of MGT, reported Alwin Krämer, MD, of the German Cancer Research Center in Heidelberg, and coauthors in .

"The results of the trial suggest that early CGP by tissue-based or liquid-based testing, or both, and incorporation of MGT into the treatment armamentarium of first-line therapy improves progression-free survival in patients with CUP," the authors wrote of the findings. "Given the overall poor prognosis of unfavorable CUP and the high risk of rapid clinical deterioration of patients with this malignancy, the window of opportunity for MGT might otherwise be missed."

"Accordingly, incorporation of CGP into first-line therapy is also supported by the limited success of earlier precision oncology trials such as and , which included only patients with heavily pretreated, advanced cancer," the researchers continued. "Moreover, a next-generation sequencing study including patients with CUP has shown that, because of interim worsening of performance status, MGT could be implemented in only very few patients, highlighting the benefit of the approach used in CUPISCO (i.e., treating patients with chemotherapy while awaiting next-generation sequencing results)."

The findings are consistent with those of a recently reported study from China, which showed 3-month improvement (9.6 vs 6.6 months) in PFS for CUP treated on the basis of genomic profiling results.

CUP accounts for 2-3% of all metastatic cancers and encompasses diverse cancer types, noted the authors of an about the CUPISCO study. About 80-85% of the cancers do not have clinical/histologic features suggestive of a primary site. The patients are treated with a broad-spectrum of platinum-based chemotherapy, which leads to poor outcomes.

"The CUPISCO trial confirms the beneficial role of a biomarker-driven approach in selected patients with CUP following standard chemotherapy and marks a significant stride towards better outcomes," wrote Elie Rassy, MD, of Gustave Roussy Institute in Villejuif, France, and coauthors. "Therapies based on the molecular evaluation of tissue or blood biopsies represent a practice-changing step forward in the management of patients with CUP, although additional clinical research is necessary and agnostic approvals are warranted to move further forward."

Noting the historical use of platinum-based chemotherapy for CUP, Krämer and coauthors said the ability of first-line treatment guided by CGP to improve outcomes in CUP remained unknown. CUPISCO was designed to compare MGT and platinum-based chemotherapy in newly diagnosed unfavorable CUP.

Investigators at 159 sites in 34 countries outside the U.S. enrolled patients with newly diagnosed CUP, evaluated by CGP, and with disease control after induction with three cycles of platinum-based chemotherapy. Patients were randomized 3:1 to MGT (a targeted agent or the PD-L1 inhibitor atezolizumab [Tecentriq]) versus additional chemotherapy continued for at least 3 cycles. The primary endpoint was investigator-assessed PFS in the intention-to-treat population.

Data analysis included 438 patients, 436 of whom were randomized to the two treatment arms. The primary analysis showed that treatment with MGT was associated with a 28% reduction in the hazard for progression or death (95% CI 0.56-0.92, P=0.0079). The hazard reduction increased to 35% in the subgroup of patients who had an actionable molecular profile and received MGT (95% CI 0.42-0.99). Among patients without an actionable molecular profile, median PFS did not differ significantly between treatment groups (5.5 vs 4.4 months).

An interim analysis of OS yielded median values of 14.7 months with MGT and 11 months with chemotherapy.

Adverse events (AEs) occurred in a similar proportion of patients. AEs leading to discontinuation numbered 76 in the MGT arm and 17 in the chemotherapy arm, which translated into AE rates per 100 patient-years at risk of 35.9 versus 77.3. Rates of serious AEs per 100 patient-years at risk were 55.3 versus 51.5.

The authors acknowledged several limitations of the study: open-label design, variable access to CGP in participating centers, selection bias arising from limiting eligibility to patients with at least stable disease after induction, and not taking patient ancestry into account.

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