 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.

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&mdash;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.

"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.

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.

 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. 

Gagan J, et al. Next-generation sequencing to guide cancer therapy. 

Rozenblum AB, et al. Clinical impact of hybrid capture-based next-generation sequencing on changes in treatment decisions in lung cancer. 

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

Articles

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 for patients with cancer of unknown primary, as well as the challenges of identifying eligible patients for the trial, according to ESMO guidelines.

ESMO Data Show More Can Be Done for Cancer of Unknown Primary Patients

Over two years ago, women diagnosed with germline 

-mutated advanced ovarian cancer had limited treatment options, including chemotherapy or investigational treatments through clinical trials.

In late 2014, AstraZeneca was proud to introduce a new treatment option, with the US FDA accelerated approval of LYNPARZA

 (olaparib) as a monotherapy for the treatment of deleterious or suspected deleterious germline 

-mutated (as detected by an FDA-approved test) advanced ovarian cancer, for patients who have been treated with three or more prior lines of chemotherapy. LYNPARZA was the first approved poly (ADP-ribose) polymerase (PARP) inhibitor and has more than two years of patient experience. LYNPARZA has serious risks including myelodysplastic syndrome/acute myeloid leukemia, pneumonitis, and embryo-fetal toxicity. To learn more, read the Important Safety Information on the adjacent page.

More than two years since the approval of LYNPARZA, over 3,000 US women with germline 

-mutated advanced ovarian cancer have been treated with this important medicine. This wouldn’t have been possible without the many women who participated in clinical trials. Thanks to their participation, the relentless commitment of global researchers and tireless efforts by advocacy groups to raise awareness and support for funding, LYNPARZA is now an important treatment option.

Over the past decade, research in DNA Damage Response (DDR) and other areas have made considerable progress in understanding the underlying disease mechanisms in advanced ovarian cancer, and at AstraZeneca, we are humbled to have played a role in this research.

AstraZeneca is proud to be a pioneer and will continue to advance DDR research - a journey that is far from complete.

We look forward to continued collaboration with advocacy groups and health care professionals to advance ovarian cancer research.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit 

Please see Important Safety Information on following page and accompanying Brief Summary of the full Prescribing Information.

To learn more about LYNPARZA please visit 

LYNPARZA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated as monotherapy in patients with deleterious or suspected deleterious germline 

-mutated (as detected by an FDA-approved test) advanced ovarian cancer who have been treated with three or more prior lines of chemotherapy.

The indication is approved under accelerated approval based on objective response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

There are no contraindications for LYNPARZA.

Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML):

 Occurred in <1% of patients treated with LYNPARZA, and the majority of those reports were fatal. The duration of therapy in patients who developed secondary MDS/AML varied from <6 months to >2 years. In a randomized placebo-controlled trial, MDS/AML occurred in 2% of patients treated with LYNPARZA. All of these patients had previous chemotherapy with platinum agents and/or other DNA damaging agents, including radiotherapy, and some of these patients also had a history of previous cancer or of bone marrow dysplasia.

Monitor patients for hematological toxicity at baseline and monthly thereafter. Do not start LYNPARZA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤Grade 1). For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood counts weekly until recovery. If the levels have not recovered to Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. Discontinue if MDS/AML is confirmed.

: Occurred in <1% of patients exposed to LYNPARZA, and some cases were fatal. If patients present with new or worsening respiratory symptoms such as dyspnea, fever, cough, wheezing, or a radiological abnormality occurs, interrupt treatment with LYNPARZA and initiate prompt investigation. Discontinue if pneumonitis is confirmed.

LYNPARZA can cause fetal harm. A pregnancy test should be performed on all pre-menopausal women prior to treatment. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for six months after receiving the final dose.

In clinical studies, the most common adverse reactions (Grades 1-4) in ≥20% of patients included anemia (34%), nausea (75%), fatigue (including asthenia) (68%), vomiting (43%), diarrhea (31%), dysgeusia (21%), dyspepsia (25%), headache (25%), decreased appetite (25%), nasopharyngitis/pharyngitis/URI (43%), cough (21%), arthralgia/musculoskeletal pain (32%), myalgia (25%), back pain (25%), dermatitis/rash (25%), and abdominal pain/discomfort (47%).

Common lab abnormalities (Grades 1-4) included decrease in hemoglobin (90%), decrease in absolute neutrophil count (32%), decrease in platelets (30%), decrease in lymphocytes (56%), mean corpuscular volume elevation (85%), and increase in creatinine (30%).

Clinical studies of LYNPARZA in combination with other myelosuppressive anticancer agents, including DNA damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity.

Avoid concomitant use of strong and moderate CYP3A inhibitors. If the strong or moderate CYP3A inhibitor must be co-administered, reduce the dose of LYNPARZA. Advise patients to avoid grapefruit and Seville oranges during LYNPARZA treatment.

Avoid concomitant use of strong and moderate CYP3A inducers when using LYNPARZA. If a moderate inducer cannot be avoided, be aware of a potential for decreased efficacy of LYNPARZA.

 No data are available regarding the presence of olaparib in human milk, the effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in the breastfed infant, advise a lactating woman not to breastfeed during treatment with LYNPARZA and for one month after receiving the final dose.

No dose adjustment is required in patients with mild hepatic impairment (Child-Pugh classification A). There are no data in patients with moderate or severe hepatic impairment.

 No dosage adjustment is necessary in patients with mild renal impairment (CLcr 51-80 mL/min). In patients with moderate renal impairment (CLcr 31-50 mL/min), reduce the dose to 300 mg twice daily. There are no data in patients with severe renal impairment or end-stage renal disease (CLcr ≤30 mL/min).

Please see complete Prescribing Information, including Patient Information (Medication Guide). 

http://www.azpicentral.com/Lynparza/pi_lynparza.pdf

Our scientists recognized early on that this molecule showed potential. After 10 years of testing and probing hypotheses, they discovered that LYNPARZA may exploit tumor DNA damage response (DDR) pathway deficiencies to potentially kill cancer cells. The exact mechanism of action of LYNPARZA remains a subject of research.

Since the approval of LYNPARZA, over 3,000 US women with germline BRCA-mutated advanced ovarian cancer have been treated with this important medicine.

Sponsored Content

Articles

ESMO Data Show More Can Be Done for Cancer of Unknown Primary Patients

AstraZeneca: Pioneers in Ovarian Cancer