A Pilot Trial of Molecularly Tailored Therapy for Patients with Metastatic Pancreatic Ductal Adenocarcinoma

Anteneh A Tesfaye, Hongkun Wang, Marion L Hartley, Aiwu Ruth He, Louis Weiner, Nina Gabelia, Lana Kapanadze, Muhammad Shezad, Jonathan R Brody, John L Marshall, Michael J Pishvaian, Anteneh A Tesfaye, Hongkun Wang, Marion L Hartley, Aiwu Ruth He, Louis Weiner, Nina Gabelia, Lana Kapanadze, Muhammad Shezad, Jonathan R Brody, John L Marshall, Michael J Pishvaian

Abstract

Purpose: Despite the wide adoption of tumor molecular profiling, there is a dearth of evidence linking molecular biomarkers for treatment selection to prediction of treatment outcomes in patients with metastatic pancreatic cancer. We initiated a pilot study to test the feasibility of designing a larger phase II trial of molecularly tailored treatment for metastatic pancreatic cancer. Methods: Our study aimed to assess the feasibility of following a treatment algorithm based on the expression of three published predictive markers of response to chemotherapy: ribonucleotide reductase catalytic subunit M1 (for gemcitabine); excision repair cross-complementation group 1 (for platinum agents); and thymidylate synthase (for 5-fluorouracil) in patients with untreated, metastatic pancreatic cancer. Results of the tumor biopsy analysis were used to assign patients to one of seven doublet regimens. Key secondary objectives included response rate (RR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Results: Between December 2012 and March 2015, 30 patients were enrolled into the study. Ten patients failed screening primarily due to inadequate tumor tissue availability. Of the remaining 20 patients, 19 were assigned into 6 different chemotherapy doublets, and achieved an RR of 28%, with a DCR rate of 78%. The median PFS and OS were 5.78 and 8.21 months, respectively. Conclusions: The incorporation of biomarkers into a treatment algorithm is feasible and resulted in a PFS and OS similar to other doublet therapies for patients with metastatic pancreatic cancer. Based on the results from this pilot study, a larger phase II randomized trial of molecularly targeted therapy versus physicians' choice of standard of care has been initiated in the second-line setting (NCT02967770).

Keywords: chemotherapy; metastatic pancreatic cancer; molecular testing.

Conflict of interest statement

No competing financial interests exist.

Figures

FIG. 1.
FIG. 1.
Chemotherapy doublet selection algorithm and patient flow. (a) Patients were assigned therapy based on the high versus low values of RRM1, ERCC1, and TS, with cutoffs as determined by Caris. The number of patients (n) in each group is also listed. (b) The number of patients (n) in each group is also listed. 5FU, 5 fluorouracil; Abrax, nab-paclitaxel; ERCC1, excision repair cross-complementation group 1; FOLFOX, 5FU + oxaliplatin; FOLFIRI, 5Fu + irinotecan; Gem, gemcitabine; Iri, irinotecan; Ox, oxaliplatin; RRM1, ribonucleotide reductase catalytic subunit M1; Tax, docetaxel; TS, thymidylate synthase.
FIG. 2.
FIG. 2.
Percent changes in CA19-9 from pretreatment level to the nadir reported on the study.
FIG. 3.
FIG. 3.
Treatment duration and response by individual patients.
FIG. 4.
FIG. 4.
Median PFS and OS. (a) Graph showing Kaplan–Meier of PFS. The median PFS (95% CI) was 5.78 months (5.39–15.72). (b) Graph showing Kaplan–Meier of OS. The median OS (95% CI) was 8.21 months (7.16–15.72). CI, confidence interval; OS, overall survival; PFS, progression-free survival.

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