Targeted Therapies for Pancreatic Cancer

Abstract

The prognosis of patients with pancreatic cancer is extremely poor, and current systemic therapies provide marginal survival benefits for treated patients. The era of targeted therapies has offered a new avenue to search for potentially more effective strategies. Findings from phase III studies of molecular agents targeting vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) were disappointing, although results with the EGFR tyrosine kinase inhibitor erlotinib were statistically significant but clinically of marginal benefit. Ongoing trials are assessing other single targeted agents and combinations of targeted therapies combined with gemcitabine in an effort to treat the multiple molecular pathways that seem to be active in this disease. Better preclinical modeling, improved clinical trial designs with adequate pilot studies, and better patient selection in trials of interventions are needed to improve the yield from research efforts.

Pancreatic cancer remains a major cause of cancer deaths, with approximately a quarter of a million people worldwide dying annually from this disease.¹ Furthermore, the incidence is increasing by approximately 2% annually in developed countries.² About half of patients present with metastatic or end-stage disease, 35% with localized unresectable disease, and among 20% who are potentially resectable, very few will be cured. The 5-year survival rate of people with pancreatic cancer is less than 5%,³ underscoring the need for more effective systemic therapies coupled with targeted agents and strategies that can improve quality of life.

At this time, gemcitabine remains the recommended therapy for patients with advanced pancreatic cancer. However, gemcitabine treatment provides only a marginal survival benefit over no therapy. Median survival of gemcitabine-treated patients is approximately 5.5 to 6 months, with a 1-year survival rate of less than 20%.⁴ The efficacy of gemcitabine has recently been extended to the adjuvant setting as well.^5,6 The major advantages of this agent include its ease of use, favorable toxicity profile, and documented symptom improvement in up to a quarter of patients with symptomatic disease.⁴

Over the past 10 years, attempts to improve outcome of patients treated with gemcitabine by combining it with other cytotoxic agents have been unsuccessful. Most classes of drugs used in nonhematologic malignancies have been combined with gemcitabine in phase III trials, without any statistically significant survival benefit over that achieved with gemcitabine alone. Some positive trends have been detected, especially when gemcitabine is combined with platinum compounds⁷; however, meaningful improvements with combination therapy are expected only in patients with very good performance status rather than in the average patient diagnosed with advanced disease.⁸

TARGETED THERAPIES

More recently, the era of targeted therapies has generated a lot of interest in discovering better approaches for patients with pancreatic cancer. In the late 1990s, early studies were undertaken with agents such as the farnesyltransferase inhibitors and matrix metalloproteinase inhibitors. Farnesyltransferase inhibitors target the K-ras oncogene pathway, which is activated in 80% to 85% of pancreatic tumors; and overexpression of matrix metalloproteinase had been demonstrated in pancreatic tumors.⁹ While these drugs did not show any single-agent activity, they were studied in the phase III setting combined with gemcitabine or placebo.^10,11 Results were negative with no obvious scientific explanation; no studies have gone back to look at why the farnesyltransferase inhibitors, which target K-ras, were ineffective when tested clinically.

In the early 2000s, gemcitabine was subjected to combinations with secondgeneration targeted agents that, unlike the earlier drugs, had a track record of antitumor activity in common cancers such as colon, breast, and lung. Targets of these agents included the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor (VEGF).

Targeting EGFR and VEGF

Several factors supported the validity of EGFR as a target in pancreatic cancer: Research suggested that the EGFR pathway was activated in a large proportion of human pancreatic cancers based on overexpression of EGFR protein; historical data suggested the prognostic significance of EGFR ligand expression; and anti-EGFR drugs had demonstrated preclinical activity in vitro and in vivo.^12–14

There was also excitement about testing anti-VEGF strategies in pancreatic cancer. Bevacizumab, an anti-VEGF monoclonal antibody, had demonstrated efficacy in most other tumor types in which it had been studied and had resulted in encouraging data in the phase II setting in patients with pancreatic cancer.¹⁵

Unfortunately, two randomized phase III trials of monoclonal antibodies directed against EGFR and VEGF, reported at the 2007 meeting of the American Society of Clinical Oncology (ASCO), were negative.^16,17 Kindler et al presented preliminary results of the Cancer and Leukemia Group B (CALGB) 80303 study, wherein 602 advanced pancreatic cancer patients were treated with gemcitabine plus bevacizumab or gemcitabine plus placebo.¹⁶ With approximately 1 year of follow-up, median durations of overall survival, the primary end point, were 5.7 and 6.0 months for the two treatments, respectively (95% confidence intervals [CI] 4.9, 6.5/5.0, 6.9). The other negative study was the Southwest Oncology Group (SWOG) S0205 phase III trial of gemcitabine plus the anti-EGFR monoclonal antibody cetuximab vs. gemcitabine alone in patients with locally advanced or metastatic pancreatic adenocarcinoma. ¹⁷ Among 766 patients enrolled, median overall survival was 6.0 months with single-agent gemcitabine and 6.5 months with the addition of cetuximab (hazard ratio [HR] 1.09, 95% CI 0.93– 1.27, P =.14).

However, results of an earlier study testing erlotinib, an oral EGFR tyrosine kinase inhibitor, were statistically positive although clinically marginal.¹⁸ In this phase III randomized trial, 569 patients with advanced pancreatic cancer were treated with gemcitabine with or without erlotinib. Overall survival duration improved from 5.9 months with single-agent gemcitabine to 6.2 months with erlotinib added (HR 0.82, 95% CI 0.69–0.99, P = .038), and 1-year survival rate increased from 17% to 24%, respectively. These results led to approval of the gemcitabine/erlotinib regimen by the US Food and Drug Administration for patients with locally advanced and metastatic pancreatic cancer. At this time, however, this combination may not set a standard of care but is certainly a treatment option for patients with advanced pancreatic cancer. The gemcitabine/erlotinib combination also has more toxicities and higher cost relative to gemcitabine alone, which are important factors to discuss with patients when reviewing their therapeutic options.

Data from more than 1,300 patients who have participated in randomized phase III trials and large phase II trials are instructive regarding the utility of EGFR-directed therapies for pancreatic cancer: these studies show that anti-EGFR monoclonal antibodies are unlikely to add benefit, and EGFR tyrosine kinase inhibitors add a marginal benefit.^17–20 While there had been preclinical rationale for studying these agents in pancreatic cancer patients, we now know that increased EGFR protein expression is not synonymous with EGFR pathway activation; further, the prognostic significance of EGFR ligand expression has not been confirmed in large, prospective trials; and, while anti-EGFR strategies demonstrated preclinical activity in certain tumor types, the tumor models that were used may not have provided accurate guidance for the study of these agents clinically.

The next generation of single-target trials is moving toward a focus on antiangiogenic agents, including anti-VEGF and anti-VEGFR strategies, again combined with gemcitabine. VEGF trap, a high-affinity VEGF antagonist, and Axitinib, an inhibitor of VEGFR 1, 2, and 3 tyrosine kinases, are currently being tested in phase III clinical trials.

Lessons To Be Learned

The phase III trials of anti-EGFR and anti-VEGF agents in pancreatic cancer can be used to illustrate important issues in the study of molecular drugs for pancreatic cancer and other tumor types. First, we need to develop intelligent pre-phase III clinical trial designs that will provide accurate “go–no go” signals for conducting a large randomized phase III trial of a new agent. The phase III trial of gemcitabine/erlotinib vs. gemcitabine alone was not preceded by a phase II trial. On the other hand, the gemcitabine/cetuximab combination had undergone phase II testing, resulting in a 32% 1-year survival rate.¹⁹ This was an interesting signal considering the < 20% survival rate at 1 year with gemcitabine alone based on historical data. The response, median survival, and time to progression data with cetuximab were less notable, however.¹⁹ A phase II study of bevacizumab plus gemcitabine also generated promising data, with an 8.8-month median survival and 37% 1-year survival rate reported, which led to phase III testing of bevacizumab.¹⁵ However, the study population in the phase II bevacizumab study was selected by the exclusion of patients with some known poor prognostic features, such as history of thromboembolism. The encouraging phase II indices were not borne out in phase III trials, underscoring the need for better survival surrogates or signals to proceed to advanced stage trials that will avoid the time and expense of unsuccessful studies.

Whether gemcitabine is the optimal partner for targeted therapies is another question that deserves further exploration. Other agents and combinations, including ixabepilone, S-1, nanoparticle albumin-bound (Nab)/paclitaxel, FOLFOX (5-fluorouracil, leucovorin, oxaliplatin), and XELOX (capecitabine, oxaliplatin) have shown activity in pancreatic cancer and may be better partners with targeted agents.

Furthermore, patients with pancreatic cancer have been lumped together in studies of interventions, regardless of the stage of their disease. This is inappropriate because the tumors have different biologies and different behaviors, which can confound analysis of data and interpretation of results. Most researchers now agree that patients with locally advanced vs. metastatic disease are two distinct populations that should be studied separately.

BEYOND SINGLE TARGETS

Unlike some cancers that have been successfully treated with a single targeted agent, such as imatinib therapy for gastrointestinal stromal tumors (GIST) or trastuzumab for HER2-amplified breast cancer, pancreatic cancer involves multiple genetic mutations not easily treated with a single agent.²¹ The substantial redundancies and crosstalk of cell signaling pathways further confound the concept of targeting one pathway to improve outcomes for patients with this disease.

In this regard, studies of combinations of multiple targeted therapies with gemcitabine in patients with pancreatic cancer are ongoing or planned (Table 1). Some of these strategies are aimed at different molecular pathways and others target different points along the same pathway. For example, a study at the University of Chicago, of bevacizumab + gemcitabine + either erlotinib or cetuximab, includes both EGFR and VEGF inhibitors. In a North Central Cancer Treatment Group (NCCTG)/Mayo Clinic trial, panitumumab and erlotinib are being combined with gemcitabine in an attempt to treat different points along the EGFR pathway. Other trials are assessing Src inhibitors or inhibitors of two erbB receptor family members. The SWOG is launching a randomized phase II trial of gemcitabine/erlotinib with or without the insulin-like growth factor 1 receptor (IGF1R) monoclonal antibody in patients with metastatic-only pancreatic cancer. Collaborators at Karmanos Cancer Institute and M. D. Anderson Cancer Center are evaluating genestein, which has been shown in vitro and in animal in vivo experiments to inhibit the Akt pathway and NFκB – components of resistance to chemotherapy and also to EGFR blockers.

Table 1.

Selected ongoing or planned studies of multi-targeted combination regimens for patients with pancreatic cancer.

Study Group	Target	Agents
University of Chicago	EGFR + VEGF	Gemcitabine + bevacizumab + erlotinib or cetuximab
NCCTG/ Mayo Clinic	EGFR “double hit”	Gemcitabine + panitumumab + erlotinib
Brown University & Sarah Cannon Cancer Center	HER family “double hit”	Gemcitabine + lapatinib
Karmanos Cancer Center & MDACC	EGFR + Akt/NFκB	Gemcitabine + erlotinib + genestein
SWOG (Randomized phase II)	IGF1R + EGFR	Gemcitabine + erlotinib ± anti-IGF1R monoclonal antibody

Abbreviations: CALGB = Cancer and Leukemia Group B; EGFR = epidermal growth factor receptor; IGF1R = insulin-like growth factor 1 receptor; MDACC = M. D. Anderson Cancer Center; NCCTG = North Central Cancer Treatment Group; SWOG = Southwest Oncology Group; VEGF = vascular endothelial growth factor.

CONCLUSION

The field of research in pancreas cancer remains wide open. There is a need for better preclinical modeling for optimum study design that is based on science rather than empiricism. Intelligent pre-phase III clinical trial designs that will provide accurate signals in terms of proceeding to phase III trials also need to be developed. We need to refine the patient populations in which we test new approaches based on tumor burden and predictive markers, the latter of which are lacking.

Until the predominant mutations that may be operating in individual patients are better understood, it is unlikely that treating a single target will achieve a major response for patients with pancreatic cancer. Based on the multiple genetic mutations that drive this tumor, the development of multiple targeted therapies that could be delivered with the knowledge of the tumor’s molecular abnormalities would be the goal. Challenges to the development of combination targeted therapies include pharmacokinetic and pharmacodynamic considerations and the potential for drug interactions that might increase toxicity or negate the effects of a drug. Economic factors are also important and may be looked at in terms of the dollar cost vs. the clinical benefit added.