Phosphoinositide-3-kinase (PI3K)–mTOR pathway inhibitors

The PI3K/Akt/mTOR pathway is activated in half of pancreatic cancers, and inhibition of this pathway has been found to have antitumor effects in preclinical studies. Wolpin et al conducted a phase II trial evaluating the efficacy and safety of everolimus, an oral mTOR inhibitor, in patients who experienced treatment failure on first-line therapy with gemcitabine.67 Although treatment with everolimus was well tolerated, no complete or partial responses were observed, and only seven of 33 patients (21%) had stable disease at the first restaging scans performed at 2 months. The median PFS and OS was 1.8 and 4.5 months, respectively.

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Src, a nonreceptor tyrosine kinase, interacts with the PI3K regulatory subunit p85 to yield an increase in Akt activation. The oral Src inhibitor saracatinib exhibited antitumor activity in preclinical models of pancreatic cancer. In a phase II clinical trial of saracatinib in patients previously treated for pancreatic cancer, saracatinib was administered orally and continuously in 28-day cycles.68 As only two patients (11%) patients survived for at least 6 months, the study was amended as a biomarker-driven trial. However, of the 47 patients screened, only one patient was biomarker positive. Reflecting the low frequency of biomarker-positive patients, the study was eventually terminated.

Some other targeted agents, including flavopiridol (CDK inhibitor), celecoxib (selective COX-2 inhibitor), Rexin-G (targeted gene therapy vector), and PX-12 (inhibitor of thioredoxin-1), have been tested as either single agents or in combination with cytotoxic therapy in the second-line setting.69–72However, most of these drugs resulted in minimal or modest antitumor activity, except for Rexin-G. As a tumor-targeted retrovector bearing a cytocidal cyclin G1 product, Rexin-G is a paradigm in the length of time to bring new therapeutics to bedside. It is the first targeted gene therapy vector to gain fast-track designation and orphan drug priorities for multiple cancer indications in the USA. As for pancreatic cancer, Rexin-G showed promise in the treatment of gemcitabine-resistant metastatic pancreatic cancer, as it produces an almost 10-month survival benefit. A pivotal phase II/III two-arm randomized study has been planned to confirm the OS benefit of Rexin-G as monotherapy versus the physician’s choice of therapy in gemcitabine-refractory pancreatic cancer.

Overall, using single or combination targeted agents in the second-line setting has yielded rare responses, short PFS and OS times, and has limited the value with this strategy. Slightly more activity has been observed for combining a targeted agent with cytotoxic therapy in the refractory disease setting, although the benefit may relate to the cytotoxic backbone. In addition, an assessment of biomarkers that might identify the patient subsets most likely to benefit from targeted therapy is needed.

Treatment effect trends over time

The above-summarized trials with available data were analyzed for treatment effect trends over time. The outcome trends over time were analyzed through the locally estimated scatterplot smoothing (LOESS) method using SPSS 19.0 software (IBM Corporation, Chicago, IL, USA). The median OS, PFS, and response rates of each regimen were plotted over time based on the year the studies were initiated. Regrettably, the median OS, PFS, and response rates remained unchanged over time (Figure 2).

(To view a larger version of Figure 2, click here.)


Ongoing trials in the second-line setting: finding diamonds in the rough

As the search continues for strategies to refine approaches in treating patients with pancreatic cancer, and only a few studies have focused on second-line therapy. This phenomenon is attributed to the poor performance status of the patients and limited survival benefit of testing agents or regimens after progression of first-line therapy. Nonetheless, there are still some novel noncytotoxic agents showing therapeutic potentials in this setting (Table 5).

(To view a larger version of Table 5, click here.)

Acalabrutinib, a selective second-generation BTK inhibitor, showed promising antitumor effects in combination with pembrolizumab.73 A phase II study evaluating acalabrutinib alone or in combination with pembrolizumab is currently ongoing. Preliminary results of the first 58 treated patients revealed that the combination of acalabrutinib and pembrolizumab has a favorable benefit/risk profile and encouraging antitumor activity in pretreated metastatic pancreatic cancer, particularly in a subpopulation of patients with familial pancreatic cancer.

ERY-ASP – a new investigational medicinal product composed of Escherichia coli L-asparaginase encapsulated in erythrocytes – has shown potential efficacy in a subgroup of patients with pancreatic cancer with null/low asparagine synthetase (79.4%).74 In an ongoing phase II trial, the combination of ERY-ASP plus cytotoxic chemotherapy versus chemotherapy alone is currently being tested.

Similarly, poly (ADP-ribose) polymerase (PARP) inhibitors also hold promise in the treatment of pancreatic cancer. Several trials investigating PARP inhibitors that include olaparib, veliparib, and rucaparib are underway for patients with pretreated advanced pancreatic cancer. Some have, shown encouraging results in patients with a germline BRCA1/2 mutation.

In immunotherapy studies, AM0010 – a pegylated recombinant human interleukin 10 – has shown evidence of antitumor activity as salvage therapy in metastatic pancreatic adenocarcinoma. In a phase Ib study, AM0010 plus FOLFOX resulted in a median PFS of 3.5 months and a median OS of 10.0 months. The observed immune activation, including clonal T-cell expansion and prolonged objective tumor responses, is encouraging, and this regimen is currently being studied in a phase III trial. Besides, pembrolizumab, a type of immunotherapy that works by blocking the programmed death receptor-1 (PD-1) pathway, has been recommended to treat microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) tumors in the second-line setting.75