EGFR inhibitors

Erlotinib – the most studied targeted agent – has been evaluated in the setting of gemcitabine-refractory metastatic pancreatic cancer in patients. A phase II trial of erlotinib dose-escalation to induce rash in non-selected patients with advanced pancreatic cancer showed a correlation between rash and disease control, with 47% of evaluable patients with grade 2 or 3 rash showing stable disease over 8 weeks versus 9% of patients with grade 0 or 1 rash (P = 0.017).51 However, there was no difference in survival based on rash, with a median OS of 3.9 months for patients who developed grade 2 or 3 rash versus 3.8 months for patients with grade 0 or 1 rash (P = 0.12). In addition, no differences in median TTP by degree of rash were noted (P = 0.25). Erlotinib combined with chemotherapeutic drugs or other targeted agents has also been tested in the second-line setting. A phase II trial studied erlotinib in combination with capecitabine in 30 gemcitabine-refractory patients and showed an overall objective radiologic response rate of 10% and median survival duration of 6.5 months.52 In another phase II trial, the safety and efficacy of selumetinib, a MEK 1/2 inhibitor, plus erlotinib in patients with previously treated advanced pancreatic cancer were evaluated on the basis of preclinical evidence of synergistic activity between MEK and EGFR inhibitors.53 This dual-targeted therapeutic strategy showed modest antitumor activity in pancreatic cancer, with a disease control rate of 41% and a median OS of 7.3 months. Dual inhibition of the EGFR and VEGF pathways using the combination of erlotinib and bevacizumab has also been tested for gemcitabine-refractory metastatic pancreatic cancer.54 With a median OS of 102 days and median TTP of 40 days, the authors concluded that this “targeted-only” approach was relatively ineffective for this patient population. Everolimus, an mammalian target of rapamycin (mTOR) inhibitor, and erlotinib in combination were also evaluated as another dual-targeted regimen.55 The researchers reported a median OS of 87 days (2.9 months), with no objective response or disease stability.

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Gefitinib, another EGFR TKI, was shown to enhance the activity of various cytotoxic agents, including taxanes, in preclinical studies. Ignatiadis et al, therefore, conducted a phase II trial using a gefitinib and docetaxel combination as second-line treatment in patients with advanced pancreatic cancer.56 The study enrolled 26 patients and showed a median OS of 2.9 months, with 34.6% of patients developing grade 3/4 neutropenia (only one developed febrile neutropenia). A similar study done by Brell et al also showed limited efficacy. Notably, febrile neutropenia was observed in 11 patients (27%).57

Lapatinib is a TKI that binds to both EGFR and HER-2, which is overexpressed in 20% of patients with pancreatic cancer. Lapatinib leads to cell-growth arrest by the dual inhibition of EGFR and HER-2 and apoptosis via the inhibition of HER-2. Based on preclinical data suggesting augmented inhibition of tumor progression by targeting EGFR and HER-2 in xenograft models, Wu et al treated 17 patients with metastatic pancreatic cancer, who had progressed during first-line gemcitabine-based therapy, with capecitabine at 1,000 mg/m2 on days 1–14 in combination with lapatinib 1,250 mg daily on a 21-day cycle.58 A disease control rate of 35.3% was achieved, with median PFS and OS rates of 2.6 and 5.2 months, respectively. Furthermore, the researchers observed that a subset of patients who responded to the lapatinib and capecitabine showed prolonged PFS (4.0 months) and OS (8.3 months).

VEGF and VEGFR inhibitors

Bevacizumab – an anti-VEGF monoclonal antibody – has been approved for the treatment of various solid tumors (colon cancer, non-small-cell lung cancer, and renal cancer) and a specific eye disease. A previous phase III trial comparing gemcitabine plus bevacizumab with gemcitabine alone in the first-line setting showed no improvement in OS with the addition of bevacizumab to gemcitabine.59 In the second-line setting, patients with gemcitabine-refractory metastatic pancreatic adenocarcinoma were randomized to receive bevacizumab alone or bevacizumab in combination with docetaxel.60 The median PFS and OS were 43 days (1.4 months) and 165 days (5.5 months) in the combination group and 48 days (1.6 months) and 125 days (4.2 months) in the single-agent group. No confirmed objective responses were observed, and the study was terminated according to the early termination rule for futility.

Sunitinib is an oral, small-molecule, multi-targeted receptor TKI that inhibits VEGFR, PDGFR, kit, RET, and FLT3. The Cancer and Leukemia Group B conducted a phase II study evaluating sunitinib in 77 patients with progressive metastatic pancreatic cancer following prior gemcitabine-based therapy.61The disease control rate was 21.7%: one patient (1.4%) had a partial response, and 15 patients had stable disease (20.3%). The PFS was 1.31 months and OS was 3.68 months. Although the study met its primary endpoint (disease control rate), the researchers concluded that sunitinib had minimal activity and moderate toxicity in a population of patients with gemcitabine-refractory pancreatic cancer.

Vatalanib is an orally active TKI with high receptor-binding affinity for VEGFR, PDGFR, c-Kit, and c-Fms. In preclinical orthotopic pancreatic models, vatalanib showed significant antitumor activity and it was correlated with decreased microvessel density. As vatalanib targets multiple targets implicated in pancreatic cancer survival and angiogenesis and shows promising preclinical activity, a phase II study investigating the efficacy and tolerability of vatalanib in patients with gemcitabine-refractory advanced pancreatic cancer was conducted.62 The study resulted in a 6-month survival rate of 29%, with a median PFS of 2 months. The most common grade 3/4 adverse events included hypertension (20%), fatigue (17%), abdominal pain (17%), and elevated alkaline phosphatase (15%). Changes in biomarkers, including soluble VEGF and VEGFR, did not correlate with the response to vatalanib.

Ras pathway inhibitors

The Ras pathway represents a growth-promoting pathway that is associated with pancreatic cancer through mutations in the KRAS and BRAF genes. Activating KRAS mutations are observed in >90% of pancreatic adenocarcinomas. Reflecting the complexity of directly targeting KRAS, drug development efforts have focused on downstream components of the Ras pathway, such as MEK. Selumetinib is an oral MEK1/2 inhibitor, and a free-base suspension of selumetinib has demonstrated preclinical activity in a range of tumors, including human pancreatic tumors. In a randomized phase II study, 70 patients with metastatic pancreatic cancer, who failed first-line therapy, were administered either selumetinib or capecitabine.63 The median OS was 5.4 months in the selumetinib group and 5.0 months in the capecitabine group (P = 0.92). The median PFS was 2.1 and 2.2 months in the selumetinib and capecitabine groups, respectively (P = 0.41). Serious adverse events were recorded in 43% of patients in the selumetinib group and 25% in the capecitabine group. These researchers concluded that although selumetinib is a well-tolerated second-line option for metastatic pancreatic cancer patients with failed first-line gemcitabine treatment, selumetinib is not significantly different from capecitabine in terms of OS in this patient population. Furthermore, the dual-targeted therapeutic strategy using selumetinib and MK-2206 failed to improve OS in the second-line setting.64

Janus kinase inhibitors

Emerging evidence supports a role for Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling in the pathogenesis and clinical course of pancreatic cancer. In a randomized phase II study, the JAK1/JAK2 inhibitor ruxolitinib was evaluated in combination with capecitabine versus placebo plus capecitabine in patients who experienced treatment failure with gemcitabine.65 No difference in survival was observed in the intention-to-treat population. However, in a prespecified subgroup analysis, patients with a C-reactive protein (CRP) level greater than 13 mg/L showed an improvement in median OS (2.7 vs 1.8 months; P = 0.011). This finding led to the design of two randomized phase III trials (JANUS1 and JANUS2) for the second-line treatment of advanced pancreatic cancer. However, both JANUS1 and JANUS2 studies were terminated due to the lack of efficacy (no survival benefit for ruxolitinib plus capecitabine).66