Tamara Saurí, MD
Genomic and proteomic characterization of pancreatic cancer tumors can effectively be used to prescreen patients for clinical trials exploring molecularly matched targeted therapies, according to researchers from Vall d’Hebron University in Barcelona, Spain.
In a few cases explored in an early phase trial, molecularly matching therapies to patients’ unique tumors yielded a definite treatment benefit, reported Tamara Saurí, MD, of the Molecular Therapeutics Research Unit at Vall d’Hebron Institute of Oncology, at the 2016 Gastrointestinal Cancers Symposium.
“We saw an overall survival difference of 7 months for patients matched with a drug according to their mutation,” said Saurí in an interview with OncLive
Advanced pancreatic cancer has a “dismal” prognosis, the investigators noted. The hope is that molecular screening can identify genetic characteristics that lend themselves to targeted treatments, Saurí explained.
In the study, molecular screening was performed on archived tumor samples, which were analyzed for selected gene mutations using mass spectrometry at first and then subsequently next-generation sequencing. PTEN and PD-L1 expression levels were measured with immunohistochemistry. The aim of the molecular screening was to identify potentially targetable alterations in patients eligible for clinical trials with matched targeted therapies.
Between 2010 and 2014, the trial evaluated 86 patients with chemotherapy- refractory pancreatic cancer. Of these, 61 patients (71%) had adequate tumor tissue, using formalin-fixed paraffin-embedded samples for profiling (ie, detection of specific molecular aberrations, either from the primary site or metastatic site in 16%). All demographic, treatment, and survival data were extracted retrospectively from electronic medical records. Patients’ median age was 60 years (range, 29-78); 69% were diagnosed with early-stage disease and 31% with locally advanced or metastatic disease. The median number of treatment lines before profiling was 2 (range, 1-5).
The most common potentially targeted alterations in the 61 patients were KRAS
mutation (n = 42), with the G12D
mutation comprising 62% of these KRAS
alterations. Additionally, the study identified low PTEN expression in 4 patients and PTEN loss in 9 patients. CDKN2A
were mutated in 2 patients each and RNF43
were mutated in one patient each.
“Most of these alterations were typical of the biology of pancreatic cancer,” Saurí noted.
A total of 30 patients were enrolled in phase I trials following molecular profiling, 10 of which received a targeted therapy matched to their specific tumor alteration. These included 5 patients treated with a PI3K pathway inhibitor, 3 with a PI3K inhibitor plus a MEK inhibitor, one with anti-PD-L1 agent (a patient with high PD-L1 expression), and one with an HDM2 inhibitor (a TP53
One patient had a partial response to targeted treatment—a patient with PTEN loss who received a PI3K inhibitor plus chemotherapy. Stable disease was achieved in an additional 4 patients, including 3 receiving a PI3K inhibitor (with/without chemotherapy) and one with a PI3K inhibitor plus a MEK inhibitor.
Median time on treatment with matched therapy was 2.5 months for the trial population. Time to progression was 5.1 months. Notably, patients treated on the phase I trial had a significantly longer time from recurrence or metastasis to death. In the matched therapy arm the median survival was 19.2 months compared with 12.8 months for patients not entered on the matched-treatment trial (P
Saurí added that the targeting of pathways—blocking their effects—is probably more important in pancreatic cancer than targeting mutations. The main mutation—KRAS
—actually has no available targeted agent.
As a case study demonstrating the success of the approach, the researchers presented data from a 55-year-old man with stage IV disease, including liver metastasis, who was refractory to standard therapy, had mutations in KRAS
, and TP53 G245fs
, and PTEN
The patient was enrolled in the phase I trial and treated with a PI3K inhibitor plus paclitaxel 80 mg/m2
weekly. After 4 cycles, he achieved a partial response, with 40% reduction in tumor. His progression-free survival was 6 months.
“We saw a big difference in the target lesions. He had much improved clinical features,” Saurí noted.
Saurí T, Macarulla T, Cabrera G, et al. Molecular prescreening (MP) to treat patients (pts) with advanced pancreatic cancer (PC) in early clinical trials. J Clin Oncol. 2016;34 (suppl 4S; abstr 272).