A phase 2 trial of personalized cytotoxic therapy based on tumor immunohistochemistry in previously treated metastatic pancreatic cancer patients

Abstract

Background: The choice of a regimen in metastatic pancreatic cancer patients following progression on 1st line therapy is empiric and outcomes are unsatisfactory. This phase II study was performed to evaluate the efficacy of therapy selected by immunohistochemistry (IHC) in these patients following progression after one or more therapies.Methods: Eligible patients underwent a percutaneous biopsy of a metastatic lesion and treatment selection was determined by IHC. The study required 35 evaluable patients (power of 86%) for detecting a true 1-year survival rate of >20%.Results: A tumor biopsy was performed in 48 of 49 accrued patients. Study therapy was not given (n=13) either due to insufficient tumor on biopsy (n=8) or due to worsening cancer related symptoms after biopsy (n=5).The demographics of evaluable patients (n=35) are male/female (59%/41%), with age range 34-78 years (median 63 years). Patients had 1-6 prior regimens (median of 2). The most common IHC targets were topoisomerase 1 or 2, thymidylate synthase, excision repair cross-complementation group 1 protein (ERCC1), and osteonectin secreted protein acidic and rich in cysteine (SPARC). Commercially available treatment regimens prescribed included FOLFIRI, FOLFOX, irinotecan, and doxorubicin. The response (RECIST) was 9%, the median survival was 5.6 months (94% CI, 3.8-8.2), and the 1-year survival was 20% (95% CI, 7-33%).Conclusions: In all patients, IHC assays resulted in identification of at least two targets for therapy and a non-cross resistant regimen could be prescribed for therapy with evidence of some benefit. An IHC based treatment strategy is feasible and needs validation in larger studies.

Value of Multiplatform Molecular Profiling (MMP) of Tumors in Clinical Practice

“…In the remaining 4 studies (involving a total of 127 evaluable patients), other outcome measures were used such as response rate (complete response [CR] rate plus partial response [PR] rate), disease control rate (CR plus PR plus stable disease [SD] rate), and 1-year survival rate. MMP-guided treatment was associated with clinical benefit in a considerable proportion of patients (20%-73%) in these 4 studies as well 16,18,20,21 . Although the studies were consistent in demonstrating that MMP provides relevant biomarker information, modifies treatment decisions, and facilitates extension of PFS [13][14][15][16][17][18][19][20][21][22][23] , they were limited by relatively modest cohort sizes, and some also by their retrospective design.…”

“…MMP-guided treatment was associated with clinical benefit in a considerable proportion of patients (20%-73%) in these 4 studies as well 16,18,20,21 . Although the studies were consistent in demonstrating that MMP provides relevant biomarker information, modifies treatment decisions, and facilitates extension of PFS [13][14][15][16][17][18][19][20][21][22][23] , they were limited by relatively modest cohort sizes, and some also by their retrospective design.…”

“…Following this pivotal study, the CMI MMP approach was incorporated into clinical practice, and reports describing additional analyses focusing on the utility of this approach were published/presented. Table 2 summarizes the Von Hoff study as well as 10 subsequent studies conducted worldwide (US, Austria, Australia, Israel, Lebanon, and Egypt) [13][14][15][16][17][18][19][20][21][22][23] . Some of these studies investigated advanced disease in specific tumor types such as gastric/esophageal 14 , pancreatic/pancreaticobiliary 15,16 , breast 17 , and salivary glands cancer 18 , whereas other studies included a variety of refractory solid cancers including rare tumors [19][20][21][22][23] .…”

“…Table 2 summarizes the Von Hoff study as well as 10 subsequent studies conducted worldwide (US, Austria, Australia, Israel, Lebanon, and Egypt) [13][14][15][16][17][18][19][20][21][22][23] . Some of these studies investigated advanced disease in specific tumor types such as gastric/esophageal 14 , pancreatic/pancreaticobiliary 15,16 , breast 17 , and salivary glands cancer 18 , whereas other studies included a variety of refractory solid cancers including rare tumors [19][20][21][22][23] . Overall, 345 patients were evaluable in the 11 studies combined.…”

“…The MMP studies suggest that patients may benefit from employing MMP in earlier lines when their performance status (PS) is good and they can still receive additional treatment. Ten of the 11 CMI MMP studies reported also on patients who could not proceed to receiving MMPguided treatment due to PS decline, disease worsening, or death [13][14][15][16][17][18][20][21][22][23] . These cases ranged from 5% to 24% of the patients who underwent MMP [15][16][17][18][19][20][22][23][24][25] .…”