Two research papers presented by Roche and Foundation Medicine at the 2019 European Society of Medical Oncology (ESMO) Annual Meeting demonstrate both the promise of an innovative precision medicine driven clinical trial (CUPISCO) for patients with cancer of unknown primary (CUP), as well as the challenges of identifying eligible patients for the trial, according to ESMO guidelines.1,2
CUP represents 3-5% of all cancer diagnoses. By definition, patients diagnosed with CUP have metastatic disease, but the specific site of the primary cancer is unknown. Consequently, traditional treatment approaches, which rely on the site of origin being known, are often ineffective. The most common treatment for CUP—six rounds of platinum-based chemotherapy—results in a median overall survival rate of less than one year.
The CUPISCO study [NCT03498521], a randomised, prospective phase II clinical trial, seeks to discover whether a better treatment for CUP might exist by comparing the efficacy and safety of molecularly guided therapy (MGT) or cancer immunotherapy, versus standard chemotherapy. The CUPISCO study builds upon prior research by Foundation Medicine, which used comprehensive genomic profiling (CGP) to identify genomic alterations in CUP patients for which targeted treatments could be applied.
In the first paper presented at ESMO this year, a retrospective analysis of 303 CUP patients revealed that 32% would have been potentially eligible for the molecularly guided targeted or immunotherapy treatment options in CUPISCO, because they exhibited a genomic alteration for which an alternative treatment may be effective. To make that determination, archival tissue from centrally reviewed CUP cases was subjected to CGP using the FoundationOne® CDx test.1
"The CUPISCO trial offers doctors the opportunity to explore new treatment approaches that are based on the specific tumour mutation rather than relying solely on the site of origin – a real game-changer for CUP patients," said Prof. Alwin Krämer, Head of Clinical Cooperation Unit Molecular Hematology/Oncology, and the CUP-syndrome task force, German Cancer Research Center (DKFZ), National Center for Tumor Diseases (NCT) and Department of Internal Medicine, University of Heidelberg, Germany.
But as promising as these findings are, a second paper presented at the congress reveals challenges in identifying and enrolling patients onto the study, who belong to the ‘poor risk prognosis’ subset of CUP, as defined by ESMO guidelines. This research outlined the barriers to enrolling patients according to standardised screening and diagnostic processes. As of 19 March 2019, 157 patients had been screened for the study, which is currently recruiting histologically confirmed poor risk CUP patients. Using ESMO guidelines, 91 of those patients, or 58%, failed the screening process, for reasons such as issues in identifying this subset of CUP patients, insufficient quality or quantity of tissue available for diagnostic workup or sequencing and the declining health of individuals due in part to delays from referral centres.2
This high screening failure rate highlights the difficulties inherent in making accurate diagnoses of poor risk CUP, and suggests that more support is needed for oncologists when it comes to rare cancers of this nature.
Prof. Krämer added, "We need a robust interconnected network that links referral centres to relevant clinical trial sites so that patients in critical conditions can gain access earlier to potentially life-saving trials."
To date, over 140 CUP patients have already enrolled in the CUPISCO trial and recruitment is ongoing in more than 30 countries across Europe, as well as Latin America, Australia, and South Korea. In all, approximately 800 patients will be enrolled.5
Although ongoing, the CUPISCO approach is already informing clinical practice. By seeking to connect insights of a patient’s tumour profile using CGP with a dedicated decision making process for individual patients, physicians are being equipped with vital intelligence on what drives the growth of cancer – helping to drive understanding of how to diagnose and treat all types of cancer including CUP.
- Ross JS, et al. Comprehensive genomic profiling (CGP) of carcinoma of unknown primary origin (CUP): Retrospective molecular classification of potentially eligible patients (pts) for targeted or immunotherapy treatment (tx) using the prospective CUPISCO trial’s criteria. Presented at: ESMO Annual Meeting; 2019 Sep 27- Oct 1; Barcelona, Spain. Abstract #1983PD.
- Pauli C, et al. A challenging task – Identifying carcinoma of unknown primary (CUP) patients according to ESMO guidelines: the CUPISCO trial experience. Presented at: ESMO Annual Meeting; 2019 Sep 27- Oct 1; Barcelona, Spain. Abstract # 2037P.
- Stella GM, et al. Cancers of unknown primary origin: current perspectives and future therapeutic strategies. J Transl Med. 2012; Jan 24:10:12.
- Fizazi K, et al. Cancers of unknown primary site: ESMO clinical practice guidelines. Ann Oncol 2015; (26 suppl 5): v133–8.
- ClinicalTrials.gov [Internet; cited 2019 Aug 4] Available from: https://clinicaltrials.gov/ct2/show/NCT03498521.
- Frampton GM et al. Development and validation of a clinical cancer genomic profiling test based on massively parallel DNA sequencing. Nat Biotechnol 2013; Nov 31(11):1023-31.
- He J, et al. Integrated genomic DNA/RNA profiling of hematologic malignancies in the clinical setting. Blood 2016; Jun 16: 3004–14.
- Gagan J, et al. Next-generation sequencing to guide cancer therapy. Genome Med 2015; Jul 29;7:80.
- Rozenblum AB, et al. Clinical impact of hybrid capture-based next-generation sequencing on changes in treatment decisions in lung cancer. J Thorac Oncol 2017; Feb 12: 258–68.
- Suh JH, et al. Comprehensive genomic profiling facilitates implementation of the national comprehensive cancer network guidelines for lung cancer biomarker testing and identifies patients who may benefit from enrolment in mechanism-driven clinical trials. Oncologist 2016; Jun 21: 684–91.