Ipilimumab and Nivolumab in Rare Tumors S1609: Neuroendocrine—Letter

Patel and colleagues report the results of the basket trial (DART) studying the checkpoint inhibitors combination, ipilimumab plus nivolumab, in a cohort of patients with neuroendocrine neoplasms (NEN; ref. 1). We commend the authors for their efforts enrolling patients with such an uncommon malignancy to a prospective trial. The trial included 32 patients with refractory nonpancreatic NEN. No tumor responses were seen in the patients with low- or intermediate-grade NEN (0/14) compared with the observed 44% response rate in the patients with “high-grade” NEN (8/18). These results are consistent with the recently reported KEYNOTE-158 study where pembrolizumab showed limited efficacy in patients with well-differentiated neuroendocrine tumors with response rate of only 3.7% (2). While the response rate of 44% in high-grade NEN is promising, applying and interpreting the findings of the DART results in clinical practice is challenging. First, as reported by the authors, the microsatellite instability (MSI) status was not available to correlate tumor responses with MSI status.

In addition, high-grade NEN (defined by Ki-67 index of >20%; also known as G3 NEN) is a very heterogeneous group comprising malignancies with a very variable prognosis and clinical behavior including well-differentiated NET (G3 NET) and poorly differentiated carcinomas (NEC; refs. 3, 4). The proportion of G3 NET versus NECs was not reported. The authors report “well-differentiated, grade 3 neuroendocrine neoplasms were eligible for this cohort…“but do not report responses per differentiation (G3 NET vs. NEC). This was probably driven by the fact that the tumor grading was based on 2010 WHO criteria and determined by local pathologists and not by central pathology review. Determining the differentiation status of G3 NENs, a crucially important determinant of prognosis, can be challenging, even by expert pathologists (5). Therefore, a central pathology review should be mandatory in future trials of patients with G3 NENs. Without knowing the outcome of patients in the different G3 NEN cohorts, it is difficult applying the results in clinical practice. Although the current WHO classification of NEN is an improvement over previous classification systems, it still leaves a lot to be desired. Future classification systems will hopefully incorporate molecular determinants of clinical behavior and be more reliable and reproducible.

See the Response, p. 2434