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  • Determination of an optimal response cut-off able to predict progression-free survival in patients with well-differentiated advanced pancreatic neuroendocrine tumours treated with sunitinib: an alternative to the current RECIST-defined response

    There is a need for optimising our currently-available tools for radiological assessment of response in patients with NETs. This could be done by (1) maximising the information provided by current standard size-based criteria (such as RECIST), (2) incorporation of morphological assessment (e.g., Choi criteria (Faivre et al, 2012)) or by (3) incorporating metabolic techniques (nuclear medicine (Sundin and Rockall, 2012)) into response assessment. This study focused on the first approach.

    This post hoc analysis is the first study to identify an alternative tumour shrinkage cut-off for definition of partial response in sunitinib-treated pNET patients. While the classical cut-off of 30% of tumour diameter reduction was shown to be too restrictive and not impacting PFS in the multivariable analysis, our proposed alternative of 10% reduction did impact PFS, even when adjusted to other prognostic factors.

    Best-response to treatment was achieved early-on in the treatment with sunitinib: at a median of 3 months to best-response, with 83.9% of patients achieving the best-response during the first 7 months of treatment. Therefore, this alternative definition of objective partial response can be used as an early marker of benefit from treatment and could impact patients’ management.

    Our results support that a reduction of 10% may be used as an accurate surrogate for PFS. Earlier studies have shown the importance of maintenance of dose intensity in sunitinib-treated patients in renal cell carcinoma (RCC) (Houk et al, 2010). We would therefore suggest that dose reduction rather than dose interruption is considered in the event of treatment-related toxicity for those patients who have achieved our suggested 10% reduction on the size of targeted lesions, in accordance with the prescribing information. Moreover, since, as mentioned above, the best-response was achieved early-on following initiation of treatment, we also argue that should patients not achieve a 10% of tumour shrinkage after 7 months of treatment, the dose of sunitinib could be increased to 50 mg daily (if well tolerated) as suggested in the sunitinib SPC (EMA, 2016) and as detailed in the phase III clinical trial protocol which stated that ‘in patients without an objective tumour response who had grade 1 or lower non-haematologic or grade 2 or lower haematologic treatment-related adverse events during the first 8 weeks, the dose could be increased to 50 mg per day’ (Raymond et al, 2011). Although dose escalation of sunitinib has been explored in RCC and gastrointestinal stromal tumour (GIST) (Patel, 2012; Ornstein et al, 2016; Shi et al, 2016), experience of doing so in pNET is limited; only 10% of patients treated with sunitinib in the phase III pivotal clinical trial had dose increased to 50 mg daily, and its impact is unclear (Raymond et al, 2011).

    Alternative response cut-offs have also been explored in the past in other malignancies such as RCC, in which targeted therapies (including sunitinib) are a cornerstone of systemic management (Thiam et al, 2010, Krajewski et al, 2011, 2014). (Krajewski et al 2011, 2014) validated a different cut-off for RECIST criteria, able to identify more accurately those patients with benefit (in terms of overall survival) from anti-angiogenic agents (including sunitinib). In keeping with our findings, a cut-off of 10% of the sum of the longest tumour diameter shrinkage on the first follow-up CT scan was predictive of outcome, however, some challenges existed such as the lack of placebo-treated patients which did not allow them to explore whether the new cut-off was a predictive factor or not (Chen et al, 2014). The fact that similar findings have been shown in small series of gastrointestinal NETs treated with somatostatin analogues provide robustness to our findings (Luo, 2017). In this series, Luo et al included 33 patients with NETs treated with SSA; the authors identified that achieving a response of 10% reduction in target lesions impacted PFS.

    Our study has some note-worthy strengths such as the fact that all data were prospectively collected as part of phase II and phase III clinical trials, in addition to the previous quality-assurance of these data for registration purposes. We also explored first which was the most informative time-point, in order to calculate the response cut-off at such time-point; this, was one of the acknowledged limitations of the previous studies in RCC (Chen et al, 2014). Although the use of morphological changes (such as Choi criteria (van der Veldt et al, 2010)) have been suggested in order to improve assessment of response to targeted therapies, the incorporation of such approaches to daily practice could be challenging due to the fact that it requires specialist radiological input for assessment of changes within density of target lesions (Faivre et al, 2012). We do therefore believe that the application of our 10% alternative cut-off could be relatively straight-forward for clinicians managing patients with pNETs in daily practice.

    Limitations of our study include the fact that our analysis was limited to the measurement of marker lesions; appearance of new lesions could not be included in our analysis since it is not included in the calculation of change in percentages of response. Whether this radiological response is a predictive factor in addition to prognostic remains unclear, since patients treated with placebo who achieved such response did benefit in terms of PFS as well. It is worth highlighting the fact that the phase III study included in this analysis was interrupted early by the independent data monitoring committee (IDMC); and that following final results and demonstration of superiority of sunitinib, cross-over was allowed. Thus, the fact that some of the patients initially allocated to the placebo arm will have been treated with sunitinib (including patients in the absence of disease progression) could also explain why some patients in the placebo arm did have radiological response to treatment and its impact on prognosis regardless of the treatment group (as shown in the multivariable analysis). This would warrant further investigations in future placebo-controlled clinical trials. Another of the limitations from our study was that different sunitinib schedules were used across the phase II and the phase III studies. We do wonder whether this could be the explanation why we were unable to replicate the differences in median PFS found in the phase III study when comparing patients who did/did not reach the 10% alternative cut-off in the phase II patient population. The higher partial response rate identified in the phase II study patients could have also contributed to this. Finally, since the limited sample size did not allow us to divide our sample in separate design and validation cohorts, our results should be validated in future prospective series or clinical trials. Finally, it could also be argued that the 10% reduction in sum of marker lesions might be included within the expected inter-observer and inter-examination variability, especially when CT scans are performed as part of the daily practice and assessed outside the setting of a prospective clinical trial. It is worth highlighting that, although we do agreed with this being a possibility we do believe it is unlikely to happen due the fact that the CT scans employed in this study were not centrally reviewed and that the assessments and measurements were based on local radiologist (therefore reflecting standard clinical practice).

    In conclusion, our results support that reduction of 10% in the measurement of marker lesions, impacts on PFS and should be considered enough to classify pNET patients as responders to sunitinib and likely to derive clinical benefit from treatment.