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Originally published as JCO Early Release 10.1200/JCO.2009.23.3098 on October 26 2009 © 2009 American Society of Clinical Oncology.
Changing the Paradigm in Conducting Randomized Clinical Studies in Advanced Pancreatic Cancer: An Opportunity for Better Clinical DevelopmentMedical Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain Pancreatic cancer constitutes the fourth leading cause of cancer-related deaths in the United States.1 Because symptoms typically occur late, most patients are diagnosed with advanced disease, and thus the prognosis for this population of patients remains very poor, with an estimated median overall survival (mOS) of only 2 to 5 months with supportive care only. Gemcitabine has been considered the standard treatment for patients with advanced pancreatic cancer since Burris et al2 demonstrated in the pivotal study that patients treated with gemcitabine had a modest, yet statistically significant, improvement in mOS (5.65 v 4.41 months, P = .0025) and a significant clinical benefit (23.8% v 4.8%; P = .0022) compared with those patients treated with fluorouracil. However, single-agent gemcitabine in multiple trials consistently achieves mOS figures of approximately 6 months, a finding that clearly indicates the need for the development of new treatment strategies. Various cytotoxic agents have been clinically investigated in combination with gemcitabine in phase I and phase II trials with promising activity. Nevertheless, when these gemcitabine-based combinations have been evaluated in randomized phase III trials compared with single-agent gemcitabine, the results have been globally disappointing. Some of these combinations have resulted in improvement in the objective response rate (RR) or progression-free survival (PFS), but they have not translated into a statistically or clinically meaningful impact on OS. This has been the case for the combinations of gemcitabine with platinum analogs.3 In contrast, some other phase III studies have been completely negative without any suggestion of increased efficacy, such as the combinations of gemcitabine with the cytotoxic agents exatecan or pemetrexed or with the targeted agents tipifarnib or marimastat.4–7 Capecitabine, an oral fluoropyrimidine, has been evaluated in combination with gemcitabine in one randomized phase II and two phase III studies. In this issue of Journal of Clinical Oncology (JCO), Cunningham et al have published the results of one of the largest studies of metastatic pancreatic cancer conducted in the United Kingdom by the Medical Research Council, comparing the combination of gemcitabine and capecitabine with gemcitabine as a single agent, the latter being considered the standard of care in this setting. Although the initial results of this study, presented at the 2005 biannual European Cancer Organisation meeting,8 were positive for the primary end point of the study OS, the more mature data of the study being published now show that the combination of gemcitabine with capecitabine has an increased RR (19.1% v 12.4%; P = .034), a statistically significant increase in PFS (hazard ratio [HR], 0.78; 95% CI, 0.66 to 0.93; P = .004) with a trend towards improvement in OS (HR, 0.85; 95% CI, 0.72 to 1.02; P = .08) over single-agent gemcitabine treatment.9 Some potential caveats of this study are related to the wide range of the inclusion criteria, with patients with either locally advanced or metastatic disease being entered—having these two populations of patients with a different prognosis3—as well as patients with either performance status 0 to 1 or 2. It has been shown that patients with poor prognosis status do not benefit from the treatment of advanced disease. These two factors, among others, may have contributed to dilute the potential benefit of the combination over gemcitabine as a single agent. Herrmann et al10 had published the results of a phase III study evaluating a similar gemcitabine and capecitabine combination over single-agent gemcitabine. This study also failed to demonstrate an advantage in OS, its primary objective. Similarly, Scheithauer et al11 had also previously published the results of a randomized phase II study comparing the combination of gemcitabine plus capecitabine with gemcitabine as a single agent, this study showing no efficacy differences between the two arms. Of note, in these two additional studies, capecitabine was administered with a lower dose intensity and the sample size of the studies was quite smaller than that of the Cunningham et al study. In the study by Cunningham et al9 in this issue of JCO, the authors have in addition performed a meta-analysis, also including the patients from the two previously published studies evaluating the combination of gemcitabine and capecitabine. The results of this meta-analysis with a total of 935 patients demonstrate a significant benefit in OS favoring the combination arm (HR, 0.86; 95% CI, 0.75 to 0.98; P = .002) over gemcitabine as a single agent. On the basis of these results the authors have concluded that the combination of gemcitabine and capecitabine can be considered a new treatment option for patients with advanced pancreatic cancer. Nevertheless, some caution has to be raised about this conclusion as the schedules and dose intensities of gemcitabine and capecitabine in the three studies that composed this meta-analysis were completely different and the three trials when considered individually do not show a significant advantage in OS for the combination arm. With the increasing knowledge of the molecular biology of pancreatic cancer, some noncytotoxic targeted agents have been evaluated in patients with this disease. Pancreatic tumors bear a high incidence of KRas mutations, reported to be as high as 95%.12,13 Therefore, K-Ras inhibition was one of the first options considered for improving the clinical activity of gemcitabine. Tipifarnib, a farnesyl-transferase inhibitor, was added to gemcitabine, but failed to demonstrate any benefit over gemcitabine as a single agent.6 In the same way, marimastat, a metalloproteinase inhibitor, combined with gemcitabine failed to demonstrate an advantage over gemcitabine alone.7
Beside K-Ras mutations, pancreatic tumors harbor deregulations in the epidermal growth factor receptor (EGFR) signaling pathway at other levels.14 Therefore, EGFR inhibitors are a drug class that has been evaluated in patients with pancreatic cancer with the highest levels of enthusiasm. Accordingly, erlotinib, a tyrosine kinase inhibitor of the catalytic domain of the receptor, and cetuximab, an immunoglobulin G1 (IgG1) chimeric monoclonal antibody directed to the ectodomain of the receptor, have been evaluated in phase III clinical trials. Moore et al15 published the results of a phase III study that included 569 patients with locally advanced or metastatic pancreatic cancer treated either with gemcitabine and erlotinib or with gemcitabine alone. The results of this study showed a statistically significant difference in OS favoring the erlotinib-containing arm (HR, 0.82; P = .038). This was the first time that any drug added to gemcitabine translated into an improvement of OS. Nevertheless, some concerns have been raised among the medical oncology community on how clinically meaningful these clinical results are for the nonselected population of patients with advanced pancreatic cancer. Consequently, several analyses have been conducted to define the population of patients that could most benefit from the addition of erlotinib to standard gemcitabine. In this regard, it was shown that those patients treated with the combination who develop grade 2 or greater skin rash have a greater benefit in mOS (10.5 v 5.5 months; P < .001), than those who develop grade 1 or no skin rash toxicity. This suggests that those patients who develop this highly specific toxicity may derive greater benefit from erlotinib-containing treatment,15 as has been also demonstrated with other EGFR inhibitors in non–small-cell lung cancer and colorectal cancer. However, other retrospective analyses of possible patient populations that could potentially achieve increased benefit from erlotinib treatment have generated some confounding results. For example, when conducting subgroup analyses by baseline stratification factors and other baseline characteristics, it seems that the females do not benefit from the addition of erlotinib, as opposed to males.15 One more challenging way to improve in the definition of populations of patients that may derive greater therapeutic benefit is to define validated predictive biomarkers of activity or resistance to targeted therapies. In this regard, a small biomarker substudy conducted in a limited group of the patients ( Aberrant angiogenesis is a determinant characteristic of almost all solid tumors. Bevacizumab, an IgG1 monoclonal antibody directed to vascular endothelial growth factor A (VEGF), has been extensively evaluated in patients with pancreatic cancer. Kindler et al presented at the 2007 American Society of Clinical Oncology annual meeting the results of the Cancer and Leukemia Group B 80303 trial, in which 602 patients with locally advanced or metastatic pancreatic cancer were randomly assigned to receive gemcitabine alone or in combination with bevacizumab. The addition of bevacizumab to gemcitabine did not translate to an improvement in OS.18 The final results of this study are also unpublished. The results of another study, AVITA trial, have been recently published in JCO by Van Cutsem et al.19 A total of 607 patients with metastatic pancreatic cancer were randomly assigned to receive erlotinib plus gemcitabine with either bevacizumab or placebo. The results of this second study have also failed to demonstrate an advantage of the addition of bevacizumab in patients with advanced pancreatic cancer. The results of these two studies are in contrast with those of other phase III studies evaluating the benefit of the addition of bevacizumab to standard chemotherapy treatments in other malignancies like metastatic colorectal cancer,20–22 breast cancer,23 and non–small-cell lung cancer.24 Other antiangiogenic agents in clinical development in phase III trials, such as axitinib (AG-013736), a VEGF receptor tyrosine kinase inhibitor (NCT 00471146), and aflibercept, a soluble VEGF-A and -B receptor (NCT 00574275), have been recently communicated to be ineffective in this setting.25a, 26a The results of these two studies add more evidence to the lack of benefit by VEGF pathway inhibition in patients with advanced pancreatic cancer. Another potential approach to promote activity in cancer treatment is derived by the abrogation of different but essential properties of the malignant cell that contribute to its growth and progression. There is a consistent biologic rationale for combining antiangiogenesis and anti-EGFR therapies in cancer treatment.25 Close relationships between these factors exist: VEGF signaling is upregulated by EGFR expression and, conversely, VEGF upregulation independent of EGFR signaling seems to contribute to resistance to EGFR inhibition. Therefore, inhibition of both pathways could improve antitumor efficacy and overcome resistance to EGFR inhibition. Preclinical studies have shown that VEGF and EGFR inhibitors can have additive effects and that combined inhibition is effective in EGFR inhibitor–resistant cell lines. In pancreatic cancer this approach is indeed supported with studies in xenograft models.26 On the basis that EGFR inhibition with erlotinib confers a marginal additive effect to standard gemcitabine treatment in patients with advanced pancreatic cancer, this double VEGF and EGFR inhibition strategy has been evaluated in at least two randomized studies: the previously discussed phase III AVITA trial19 and a randomized phase II study in which patients with pancreatic cancer were randomly assigned to receive gemcitabine and bevacizumab plus either cetuximab or erlotinib.27 This double-inhibition approach has not translated in meaningful clinical activity in any of these randomized studies in pancreatic cancer. The same approach has been evaluated in other tumor types28 including renal cell carcinoma29 and colorectal cancer30–32; in all cases the results were not favorable except for a single randomized phase II study in patients with advanced irinotecan-refractory colorectal cancer, in which the treatment with irinotecan, bevacizumab, and cetuximab was superior over irinotecan and cetuximab.32 In this issue of JCO, Starling et al33 have published the results of a phase I study with 20 patients with locally advanced or metastatic pancreatic cancer where the combination of capecitabine, erlotinib, bevacizumab, and gemcitabine has demonstrated to be safe and feasible. Moreover, the authors suggest that this combination has meaningful hints of activity with an unconfirmed RR of 50% and mOS of 12.5 months. On the basis of these encouraging results, the authors have completed a single-arm phase II study with this combination. Nevertheless, considering the negative results of two randomized studies evaluating the effect of the double VEGF and EGFR inhibition in advanced pancreatic cancer, it seems very unrealistic that the approach raised by this phase I study may derive in a meaningfully active combination in a phase III setting. As previously noted, some studies performed in advanced pancreatic cancer have shown either a trend toward or a statistically significant benefit in secondary objectives, such as RR or PFS, without demonstrating an advantage in OS, typically the primary end point of these studies. In some studies, the lack of benefit for mOS may be related to critical flaws in study design, such as an inadequate sample size, an unrealistically optimistic estimated mOS for the experimental arm or an underestimation of the mOS in the control arm, usually due to different baseline characteristics of the population included in the study. Meta-analyses seek to overcome these deficiencies by pooling patients from different studies but with similar treatment designs, thus increasing sample size in an attempt to elucidate any hidden clinical benefits of underpowered studies.34,35 Heinemann et al34 published a meta-analysis of more than 3,600 patients who had been included in phase III trials comparing gemcitabine plus an experimental drug to gemcitabine alone. The authors concluded that a significant benefit in mOS was observed when gemcitabine was combined either with platinum analogs or fluoropyrimidines, observed predominantly in patients with good performance status. In the current issue of JCO, Kulke et al36 present the results of a randomized phase II trial that has explored the efficacy and safety of gemcitabine at a fixed dose rate (FDR), or in combination with cisplatin, docetaxel, or irinotecan with the objective of identifying a promising regimen for further development in a phase III trial. This study was proposed based on the evidence from earlier clinical trials in which preliminarily evaluations of these combinations had suggested sufficient activity to warrant further development. A total of 245 patients with evidence of distant metastasis were enrolled in the study. As RR was one of the determinant objectives of the study, to avoid confounding evaluation of response in the primary tumors, where there is a high degree of fibrosis, patients were excluded if they had only locally advanced disease. Each of the four study arms resulted in similar antitumor activity (RR, 12% to 14%) and mOS (6.4 to 7.1 months). Hence, the authors concluded than none of these gemcitabine-based regimens could be recommended for further investigation as an experimental arm in a phase III trial because the results were similar to those obtained with gemcitabine as a single agent.2–11,34,35 The results of this study have to be adequately analyzed with an historical perspective, not only in the context of the current standards for the treatment of advanced pancreatic cancer but also considering the situation at the time this study was designed and the results of the clinical trials published henceforth. One strategy to optimize gemcitabine activity was conceptualized by FDR administration, allowing for maximal intracellular accumulation of the active triphosphate form of the drug. This pharmacologic strategy has been evaluated in two randomized trials. Tempero et al37 published the results of a small randomized phase II study comparing gemcitabine 1,500 mg/m2 administered as an FDR (over 150 minutes) with gemcitabine administered in a fixed short infusion of 30 minutes but at a dose higher than those label approved or typically used in clinical trials (2,200 mg/m2). Gemcitabine at an FDR was superior in OS but the patients consistently had more hematologic toxicity. The second study, the phase III Eastern Cooperative Oncology Group 6201, compared the efficacy of gemcitabine administered by the standard dose and schedule, gemcitabine in an FDR infusion or the combination of oxaliplatin plus FDR gemcitabine (GEMOX). Gemcitabine administered in an FDR was superior in OS compared to gemcitabine as a short infusion but this difference did not reach statistical significance. However, patients treated with an FDR had higher toxicity, and this administration translated into higher costs.38 This trial, recently published in JCO, had some weak points in the study design. First, patients were allowed to be included if they had either locally advanced or metastatic disease, and second, the study was designed and powered to demonstrate a 33% difference in OS, an unrealistically optimistic figure in patients with this disease. After these two studies had reported their results, the study being published by Kulke et al36 in this issue of JCO corroborates the lack of additional meaningful efficacy by the administration of FDR gemcitabine. The combination of gemcitabine and cisplatin has been additionally evaluated in a phase III study39 that randomly assigned 195 patients to receive gemcitabine or gemcitabine plus cisplatin at the same dose and schedule used in the study by Kulke et al.36 The study was considered underpowered to detect a statistically significant difference in mOS. A pooled analysis of 252 patients with advanced pancreatic cancer treated with a combination of gemcitabine with a platinum analog—either oxaliplatin or cisplatin—demonstrated a significant improvement in PFS and mOS over those patients treated with gemcitabine alone. This benefit was greater in those patients with an excellent performance status.40 Therefore, despite the equivalent results the combination of cisplatin and gemcitabine demonstrated in the study by Kulke et al,36 the combination of gemcitabine with a platinum analog has been considered by some as an acceptable treatment option for patients with advanced pancreatic cancer, especially those with an Eastern Cooperative Oncology Group performance status of 0. Finally, the combination of gemcitabine and irinotecan has been evaluated in a well-designed and adequately powered phase III study showing no advantage in PFS or OS over gemcitabine as a single agent, although the combination improved the RR (16.1% v 4.4%; P < .001).41 These results are consistent with the data reported by Kulke et al in this issue of JCO.36 Considering the negative results of these additional phase III studies published in the last years in the period between the design and final reporting of the current study published by Kulke et al,27 we would conclude that this current study does not add any paramount new information. However, this study has at least two strengths that should make us change the paradigm on how we develop new drugs or combinations of drugs in patients with advanced pancreatic cancer. This study has exploited the randomized phase II study design and taken advantage of an early go/no go decision without including a very large number of patients, as would be the case for a conventional phase III study. Using this approach, the authors have decided not to go to phase III development for any of the four experimental treatments, which was done without assuming a meaningful false-negative efficacy decision. Second, the authors have decided to only include patients with metastatic disease, excluding from the study those patients with only locally advanced disease. In considering only metastatic disease, the authors have avoided introducing bias factors related to different behavior of the disease (locally advanced v metastatic) with the added benefit that almost 85% of the patients have been rendered evaluable for RR. In the context of a randomized phase II study with a limited number of patients where the decisions to go/no go for phase III study have to be done on some occasions with a weak signal on either RR, PFS or mOS, having as many patients as possible fully evaluable for the different end points may make the study more interpretable. The obvious question arises after considering the milestones achieved in the history of the treatment of advanced pancreatic cancer: how do we now move forward in order to expand the therapeutic armamentarium and offer better treatment options to patients with advanced pancreatic cancer? This is not a question with a single answer. First, we have to improve our knowledge of the molecular pathways implicated in pancreatic carcinogenesis, invasion, and metastasis. This may allow us to better select targeted agents directed to receptors or downstream effectors deregulated in this disease, which may ultimately improve the chances that the chosen therapy successfully completes clinical development. It will be critical to obtain tumor tissue in all clinical trials to gain insights on individual molecular information and to develop prognostic and predictive biomarkers of activity or primary and secondary resistance. The ultimate goal of this approach will be not only to successfully develop new targeted agents but also to define which patients might obtain greater benefit from them. Second, we need to standardize the best approach for the clinical development plan. In this sense, the optimal design for this particular disease may be to test any clinical hypothesis in a context of a randomized phase II study and then, if a benefit signal is present, move to a well-designed and correctly powered phase III study. With this approach we will increase the chances of appropriate development without erroneously including patients in phase III studies that have no possibilities of success. Third, patients' eligibility criteria for these clinical studies have to be selected more accurately, particularly with regard to tumor stage and performance status. Advanced pancreatic cancer should no longer be considered a unique disease, as patients with locally advanced tumors have a different behavior when compared to those with metastatic disease, with better mOS,3,39,40 slower rate of progression of the disease,39–41 and probably better response to systemic therapy.3 Patients with poor performance status do not appear to benefit from cytotoxic treatment or, if they do, at a lower magnitude than patients with a good performance status. As clear benefit signals are needed to move forward from randomized phase II to phase III studies, it is crucial to include patients with baseline characteristics as homogeneous as possible. Fourth, it is probably time to question whether gemcitabine should always be considered the backbone of any new combination. Most of the studies with gemcitabine-based chemotherapy have shown an efficacy plateau. By contrast, in the last years some promising randomized phase II studies have suggested that gemcitabine-free schedules may be of particular clinical benefit.42 Fifth, it is particularly important to have wide access to the full results of phase III studies that have been completed—whether they have a positive or negative outcome—on a timely basis in peer-reviewed publications. Of note, at least two phase III studies presented in oncology meetings a minimum of 2 years ago are not yet published. And last but not least, the identification and global acceptance of surrogate end points for mOS may speed the clinical development of new strategies. In this regard, new randomized studies are evaluating surrogate end points for survival like PFS or the rate of decline of the tumor marker CA19.9, among others. In this context, the National Cancer Institute Gastrointestinal Cancer Steering Committee organized a meeting to discuss how the emerging knowledge in basic science and clinical management could be better integrated to develop rationally designed clinical trials in pancreatic cancer, thus defining the directions for clinical trials to be developed in the next 3 to 5 years. Briefly, the main objectives of the meeting were to identify the needs in clinical and translational research, to facilitate collaboration among all the investigators (clinical and basic) involved in the management of this disease, to identify strategic priorities for future clinical trials—both in advanced and early-stage disease—and to define the dissemination pathway of these advantages in the oncology community. The summary report of this meeting is being published by Philip et al43 in this issue of JCO, and the recommendations of this report should be strongly considered in any clinical trial being discussed in this disease. In the last 20 years, a large number of patients have been treated in randomized, large phase III clinical trials, but the real benefit we have achieved following this development path has been very limited. Most of the cooperative groups involved in the treatment of patients with advanced pancreatic cancer have learned these historical lessons of limited success and are implementing these new concepts in the clinical development of new therapeutic strategies. Hopefully, this change in the developmental path will translate into better options for patients with advanced pancreatic cancer. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
NOTES See accompanying articles on pages 5499, 5506, 5513, and 5660 REFERENCES
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Heinemann V, Labianca R, Hinke A, et al: Increased survival using platinum analog combined with gemcitabine as compared to single-agent gemcitabine in advanced pancreatic cancer: Pooled analysis of two randomized trials, the GERCOR/GISCAD intergroup study and a German multicenter study. Ann Oncol 18:1652–1659, 2007. 41. Rocha Lima CM, Green MR, Rotche R, et al: Irinotecan plus gemcitabine results in no survival advantage compared with gemcitabine monotherapy in patients with locally advanced or metastatic pancreatic cancer despite increased tumor response rate. J Clin Oncol 22:3776–3783, 2004. 42. Ychou M, Desseigne F, Guimbaud R, et al: Randomized phase II trial comparing folfirinox (5FU/leucovorin, irinoteca, and oxaliplatin) vs gemcitabine as first-line treatment for metastatic pancreatic adenocarcinoma: First results of the ACCORD 11 trial. J Clin Oncol 25:201; 2007 (suppl 18) abstr 4516. 43. 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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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25%) included in the phase III study reported by Moore et al
