A literature‐based study of prospective trials of neuroendocrine tumor (NET) treatments was performed to identify valid alternative endpoints for predicting median progression‐free survival (PFS) in clinical trials.
Keywords: Neuroendocrine tumor, Progression‐free survival, Objective response rate, Study design, Endpoint
Abstract
Background.
In phase II trials for neuroendocrine tumors (NETs), the objective response rate (ORR) is traditionally used as a primary endpoint. However, the validity of the ORR as a primary endpoint has never been systematically examined. Therefore, a literature‐based analysis of phase II trials for NETs was performed to identify valid alternative endpoints for predicting median progression‐free survival (PFS) in clinical trials for NETs.
Materials and Methods.
Phase II trials of medical treatment for advanced NETs were identified based on a systematic search using MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials.
Results.
A total of 22 trials were identified, and 1,310 patients and 27 treatment arms were included in the analysis. There was no significant relationship between the ORR and median PFS (r = .374; 95% confidence interval [CI], −0.051 to 0.800; p = .085). Conversely, 12‐month PFS rates showed very strong correlations with median PFS (r = .929; 95% CI, 0.831–1.027; p < .001).
Conclusion.
The results of the present analysis indicate that the ORR is not significantly correlated with median PFS and suggest that 12‐month PFS rates are good alternate endpoints for screening phase II trials for NETs.
Implications for Practice.
Phase II trials are screening trials that seek to identify agents with sufficient activity to continue development. Thus, earlier endpoints are preferable, and the objective response rate (ORR) has been traditionally used as a surrogate endpoint in phase II trials for neuroendocrine tumors (NETs). However, the present study showed that the ORR was not significantly correlated with median progression‐free survival (PFS). On the other hand, the 12‐month PFS rate showed very strong correlation with median PFS and is considered a good alternate endpoint for screening phase II trials for NETs.
Introduction
Neuroendocrine tumors (NETs) are epithelial neoplasms that exhibit neuroendocrine differentiation, and they can arise from neuroendocrine cells, which are distributed widely throughout the body. NETs are relatively rare, and a recent population‐based study reported that the annual age‐adjusted incidence rate of NETs was 6.98 per 100,000 persons. However, the incidence rate of NETs has been steadily rising, with a 6.4‐fold increase between 1973 and 2012 [1].
NETs are typically indolent neoplasms, but their prognosis is highly dependent on the stage. Dasari et al. reported that the median overall survival (OS) of localized NETs was >30 years, but that of metastatic disease was only 12 months [1]. The rate of such metastatic disease was reported to reach approximately 20% [2], and more effective treatment for such tumors is required. Given the dismal prognosis of this disease, it is critical to rapidly screen new treatments and move promising therapies forward for definitive results.
In oncology phase III trials, OS is considered the gold standard and is the most commonly used primary endpoint. However, in NETs, relatively long survival and variability of salvage treatments options after progression may complicate the use of OS as a primary endpoint [3], [4], [5], [6]. Thus, progression‐free survival (PFS) is frequently used as a primary endpoint in phase III trials for NETs. On the other hand, the primary goal in a phase II trial is to determine if there is sufficient evidence of antitumor activity to undertake a phase III trial. Earlier endpoints are preferable for phase II trials, and the objective response rate (ORR) is traditionally used as a primary endpoint. Somatostatin analogues (SSAs) [7], [8], and the molecular targeted drugs, sunitinib [9] and everolimus [10], [11], [12], have been shown to prolong PFS in NET patients, and they are widely used to control tumor growth. However, the ORR in these phase III trials was only <10%. These facts suggest that tumor stabilization rather than shrinkage may still result in survival benefit. This issue has been pointed out by Kulke et al. [6] and Halperin et al. [3], and alternative endpoints to ORR are needed. However, the validity of the ORR as a primary endpoint in phase II trials and the exploration of alternate endpoints for predicting PFS have never been systematically examined for NETs.
Therefore, a literature‐based study of prospective trials of NET treatments was performed to identify valid alternative endpoints for predicting median PFS in clinical trials. The primary endpoint of this study was to evaluate the correlation between the ORR and median PFS in subjects enrolled in phase II clinical trials of medical treatment for NETs. The secondary endpoint was to explore potential correlations between other possible alternative endpoints (e.g., disease control rate [DCR] and biochemical response rate) and median PFS.
Materials and Methods
Literature Search
Phase II clinical trials of medical treatment for advanced NETs published between January 1996 and December 2016 were identified based on a systematic search using MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials. The authors (H.I. and M.S.) independently screened each record for eligibility by examining the titles, abstracts, and keywords. The search terms included “neuroendocrine tumor,” “neuroendocrine neoplasm,” “neuroendocrine cancer,” “neuroendocrine carcinoma,” or “carcinoid”; “drug therapy” or “chemotherapy”; and “clinical trial,” “controlled clinical trial,” or “randomized controlled trial.” The bibliographies of the identified articles were then screened for additional eligible articles. Among the identified articles, reports on trials including ≥20 patients per arm were analyzed if they reported the ORR and median PFS. Excluded were studies in which any arm received chemoradiotherapy, arterial infusion chemotherapy, or peptide receptor radionuclide therapy; phase I clinical trials with a dose escalation design as the protocol; and studies that included patients with neuroendocrine cancer (NEC) defined by the World Health Organization (WHO) pathologic classification because the consensus report stated that NET and NEC should be studied separately [6]. NEC is regarded as a different entity genetically [13] and clinically [14], [15], and a correlation between ORR and both PFS and OS in clinical trials for NEC has been examined [16], [17]. The search was limited to articles published in English.
Data Collection
For each trial, the following data were extracted: first author's name; year of publication or report; trial design; medical treatment regimen; number of patients in each arm; median PFS; potential alternative markers (ORR, DCR, 6‐month PFS rate, 12‐month PFS rate, 12‐month OS rate, 24‐month OS rate, and biochemical response rate. The ORR was defined as the percentage of patients with a complete response (CR) or partial response (PR) using radiological evaluation criteria (the RECIST 1.0/1.1 or WHO criteria). The DCR was defined as the percentage of patients with a CR, PR, or stable disease. The biochemical response was defined as normalization or ≥50% reduction in elevated serum chromogranin A levels.
Statistical Analysis
The Pearson's correlation coefficient (r) was used to evaluate the correlations between median PFS and other potential alternative markers in each treatment arm using linear regression analysis. Accounting for the variability of the number of arms included in each model, adjusted R2 values were used to compare the goodness‐of‐fit of regression models. Values of r closer to 1 indicated a strong positive correlation between the endpoints, and those of R2 closer to 1 indicated that the variability of median PFS was predominantly explained by the alternative endpoints.
To investigate possible reasons for heterogeneity of correlations, subgroup analyses were conducted by publication year (before 2011 vs. 2011 or later), origin of the tumor (pancreas only vs. extrapancreatic organs included), study design (randomized trial vs. nonrandomized trial), progressive disease requirement as a protocol (required vs. not required), concomitant therapy with SSAs (allowed vs. not allowed), cytotoxic drugs used (used vs. not used), and molecular targeted drugs used (used vs. not used). Publication year was categorized as before 2011 versus 2011 or later, because study designs for NETs changed from 2011 based on pivotal studies [9], [10], [11] and a consensus report [6].
Bootstrap methods with 1,000 replications were used to estimate confidence intervals (CIs) for the correlation parameters. All p values <.05 were considered significant, and all p values were two‐sided. Data were analyzed using STATA version 15.1 statistical software (StataCorp, College Station, TX).
Results
Selection of Studies
A total of 22 phase II trials [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39] with ≥20 patients per arm were identified (4 randomized trials and 18 nonrandomized trials; Fig. 1; Table 1). The primary endpoint of 14 trials (63.6%) was the ORR, and that of 7 trials (31.8%) was PFS. The radiological evaluation criteria were based on RECIST 1.0/1.1 in 20 (90.9%), and WHO criteria in 2 trials (9.1%). The median duration of enrollment and time to study completion were 20 months and 53.5 months, respectively. Fifteen trials (68.2%) included pancreatic neuroendocrine tumor (PNET): 18 of these (81.8%) also included extrapancreatic NET, but 4 (18.2%) included PNET only. The ORR, median PFS, DCR, 6‐month PFS rate, 12‐month PFS rate, 12‐month OS rate, 24‐month OS rate, and biochemical response rate were reported in 22 (100.0%), 22 (100.0%), 20 (90.9%), 9 (40.9%), 8 (36.4%), 9 (40.9%), 6 (27.3%), and 12 trials (54.5%), respectively. A total of 1,310 patients and 27 treatment arms were included in the analysis. The reported ORR and median PFS were 12% (range, 0%–56%) and 11.3 months (range, 4.5%–26.7 months), respectively.
Figure 1.
Flow chart of studies included in the systematic review of the literature. Abbreviations: NEC, neuroendocrine carcinoma; PFS, progression‐free survival.
Table 1. Characteristics of phase II trials included in the analysis.
Extrapancreatic organs: Gastrointestinal tract, lung, thymus, kidney, and larynx.
Abbreviations: ATG, autogel; CDDP, cisplatin; FU, fluorouracil; IFN, interferon; LAR, long‐acting release; ORR, objective response rate; PEG, pegylated; PFS, progression‐free survival; STZ, streptozocin.
Correlation Between the ORR and Median PFS
There was a nonsignificant relationship between the ORR and median PFS (p = .085). The r value for the ORR and median PFS was .374 (95% CI, −0.051 to 0.800; Fig. 2). Results of subgroup analyses are summarized in Figure 3. Although the correlation between the ORR and median PFS was significant in study arms in which cytotoxic drugs were used (r = .625; 95% CI, 0.026–1.224; p = .041), that in study arms that used molecular targeted drugs was not significant (r = .419; 95% CI, −0.059 to 0.896; p = .086).
Figure 2.
Correlations between objective response rate and median progression‐free survival. The gray area indicates the 95% confidence interval. r denotes Pearson's correlation coefficient. Abbreviation: CI, confidence interval.
Figure 3.
Correlations between objective response rate and median progression‐free survival in subgroup analyses. Abbreviations: CI, confidence interval; r, Pearson's correlation coefficient. SSAs, somatostatin analogues.
Correlations Between Potential Alternative Markers and Median PFS
Correlations between potential alternative markers and median PFS are summarized in Table 2. The DCR, 6‐month PFS rate, and 12‐month OS rate were moderately correlated with median PFS, and the 12‐month PFS rates showed a very strong correlation with median PFS (r = .929, 95% CI, 0.831–1.027; p < .001; Fig. 4). The regression equation was median PFS = −6.139 (95% CI, −13.509 to 1.231) + 0.408 (95% CI, 0.275–0.540) × 12‐month PFS rate, and the adjusted R2 was .846. Thus, this model indicated that a 10% increase in the 12‐month PFS rate corresponded to a 4.08‐month improvement of median PFS. The 12‐month PFS rate also showed a very strong correlation with median PFS in study arms that used cytotoxic drugs and those that used molecular targeted drugs (cytotoxic drug arm r= .935; 95% CI, 0.866–1.005; p < .001; molecular targeted drug arm r = .921; 95% CI, 0.802–1.041; p < .001).
Table 2. Correlation analyses between potential alternative markers and PFS.
r denotes Pearson's correlation coefficient.
Abbreviations: CI, confidence interval; DCR, disease control rate; ORR, objective response rate; OS, overall survival; PFS, progression‐free survival.
Figure 4.
Correlations between the 12‐month progression‐free survival (PFS) rate and median PFS. The gray area indicates the 95% confidence interval. r denotes Pearson's correlation coefficient. Abbreviation: CI, confidence interval.
Discussion
The present study showed that the ORR was not significantly correlated with median PFS for subjects in NET medical treatment clinical trials. On the other hand, the 12‐month PFS rates showed a very strong correlation with median PFS. Molecular targeted drugs and SSAs were widely used for treatment of NETs. Although the ORR in phase III trials of these treatments did not reach 10%, these agents resulted in prolongation of PFS in pivotal studies. Furthermore, it has been reported that these agents preserve patients' health‐related quality of life [40]. This fact suggests that tumor stabilization rather than shrinkage may still result in clinical benefit for NETs. The ORR has been traditionally used as a primary endpoint in phase II trials for NETs. The advantage of the use of the ORR is that it requires short follow‐up periods and a small trial population. However, the present study shows that the ORR is not an appropriate endpoint for screening phase II trials.
Phase II trials are screening trials that seek to identify agents with sufficient activity to continue development. Although definitive phase III trials for NETs use PFS as a primary endpoint, it requires long follow‐up periods and a large trial population. As a result, it renders a clinical trial both time‐consuming and costly. Rapid screening phase II trials are essential for efficient and cost‐effective development of new therapeutic agents. Thus, earlier endpoints are preferable for phase II trials, and tumor shrinkage evaluated according to RECIST, the ORR, has been traditionally used as a surrogate endpoint. The basic assumption for the use of the ORR has been that a higher rate of response is predictive of improvements in survival, and that an agent would not benefit patients without resulting in significant tumor shrinkage [41], [42], [43]. This assumption generally appears to hold true for cytotoxic drugs. However, use of the ORR as a primary endpoint in phase II trials with new agents with a modest ORR (e.g., SSAs or molecular targeted drugs) could result in a potentially effective therapy being missed. Subgroup analyses showed that the ORR is correlated with median PFS in study arms that used cytotoxic drugs, but it was not correlated in study arms that used molecular targeted drugs. These facts supported our idea.
The lack of a correlation between tumor response and survival benefit is well described. Novel agents with a modest ORR, such as molecular targeted drugs, sometimes result in prolongation of median PFS or OS in phase III trials. The putative Raf kinase and antivascular agent sorafenib used for renal cell carcinoma and hepatocellular carcinoma is a known example of such novel agents. In phase II trials of sorafenib, the ORR based on RECIST was only <5% [44], [45]. However, subsequent phase III trials showed significant prolongations of both PFS and OS [46], [47]. The simple categorization of patients into responders and nonresponders based on tumor shrinkage may fail to identify potentially promising agents with antineoplastic activity. Thus, alternative or complementary endpoints for predicting PFS or OS are required. In the present analysis, the median duration of enrollment and time to study completion were 20 months and 53.5 months, respectively. Obviously, it requires a longer time to complete phase II trials for NETs. The present study showed that 12‐month PFS rate had very strong correlations with median PFS in both subgroups that used molecular targeted drugs and those that used cytotoxic drugs. It has been shown that the 12‐month PFS rate is also correlated with OS [4]. Thus, the 12‐month PFS rate is considered a good alternate endpoint for screening phase II trials in advanced NETs, and it may contribute to accelerating development of new therapeutic agents via rapid study completion.
This study had some limitations. First, the analysis relied on summary data from published trials to assess and explore alternative endpoints, so individual patient data were unavailable for analysis. It has already been reported that trial‐level surrogacy is not necessarily reflective of individual‐level outcomes [48], so the present data cannot be used to predict an individual's chance of survival on the basis of their response to treatment. The second limitation is the small number of prospective studies, especially randomized trials, available for NETs, a factor that likely contributes to the heterogeneity of the clinical trials. Finally, the study lacked optimal statistical power and should therefore be considered only an exploratory investigation. NETs are relatively rare, and they tend to exhibit indolent progression, both of which could complicate recruiting for, and completion of, clinical trials. However, the use of the 12‐month PFS rate instead of the ORR in phase II trials for NETs would allow for faster development and earlier implementation of new therapeutic agents via rapid study completion.
Conclusion
The results of the present analysis indicate that the ORR was not significantly correlated with median PFS for subjects in NET medical treatment clinical trials. On the other hand, 12‐month PFS rate showed very strong correlation with median PFS and is considered a good alternate endpoint for screening phase II trials in advanced NETs.
Author Contributions
Conception/design: Hiroshi Imaoka
Collection and/or assembly of data: Hiroshi Imaoka, Mitsuhito Sasaki
Data analysis and interpretation: Hiroshi Imaoka
Manuscript writing: Hiroshi Imaoka
Final approval of manuscript: Hiroshi Imaoka, Mitsuhito Sasaki, Hideaki Takahashi, Yusuke Hashimoto, Izumi Ohno, Shuichi Mitsunaga, Kazuo Watanabe, Kumiko Umemoto, Gen Kimura, Yuko Suzuki, Motoyasu Kan, Masafumi Ikeda
Disclosures
Masafumi Ikeda: Novartis Pharma K.K. (RF, H), Novartis Pharma K.K., Teijin Pharma, Nobel Pharma (SAB). The other authors indicated no financial relationships.
(C/A) Consulting/advisory relationship; (RF) Research funding; (E) Employment; (ET) Expert testimony; (H) Honoraria received; (OI) Ownership interests; (IP) Intellectual property rights/inventor/patent holder; (SAB) Scientific advisory board
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