Reply to “The Randomized, Phase 2 LuCAP Study”

REPLY: We appreciate the opportunity to respond to the comments on our phase 2 LuCAP trial and thank Tuncel et al. for their thoughtful insights. The LuCAP trial evaluated low-dose capecitabine as a radiosensitizer for ¹⁷⁷Lu-DOTATATE in grade 1/2 advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs). The primary endpoint, objective response rate, was 33.3% in the combination arm versus 30.6% in the monotherapy arm, a nonsignificant difference (1). Given the overall negative results, subgroup analyses in limited samples must be interpreted with caution.

Tuncel et al. suggest improved responses with capecitabine in patients with a Ki-67 of at least 10% and pancreatic neuroendocrine tumors (NETs). However, the reported risk ratios (<1) indicate a lower probability of the outcome, that is, response with add-on capecitabine in these subgroups, not an improvement. More importantly, the 95% CIs crossed the line of no effect, confirming nonsignificance. We acknowledge that our study comprised a small proportion of patients with pancreatic NETs and Ki-67 values of at least 10%, and hence, the subgroup analyses were not adequately powered for meaningful interpretations.

Tuncel et al. also propose higher-dose capecitabine and temozolomide. However, capecitabine was used as a radiosensitizer in this study, not as a definitive therapy in itself. The 1,250 mg/m² dose was consistent with prior studies and more appropriate for our patient population (2–5). While CAPTEM (capecitabine plus temozolomide) is an effective treatment regimen for NETs, its combination with ¹⁷⁷Lu-DOTATATE has primarily been explored in high-grade and FDG-avid tumors (6,7). Moreover, temozolomide’s long-term risk of myelodysplasia makes its omission justified in our study, which included only grade 1/2 GEP-NETs and excluded patients with discordant somatostatin receptor–negative, FDG-positive disease (8).

We agree that longer follow-up is needed for survival analysis, and the same is planned. However, our findings remain robust, particularly in gastrointestinal NETs with a Ki-67 less than 10%, indicating that capecitabine does not enhance response rates in these indolent tumors. Further studies are indeed required for higher-grade tumors and pancreatic NETs. However, we must emphasize here the results of the subgroup analyses of the phase 3 NETTER-2 trial, wherein objective response with ¹⁷⁷Lu-DOTATATE was higher in patients with grade 3 NETs (48.1% vs. 40.4% in grade 2) and pancreatic NETs (51.2% vs. 26.7% in small-bowel NETs), although the progression-free survival was expectedly lower in these subgroups (9). Considering these findings, it is important that future studies carefully evaluate the long-term benefits and risks of combining chemotherapy with ¹⁷⁷Lu-DOTATATE. A key question remains whether concurrent chemotherapy should be preferred with ¹⁷⁷Lu-DOTATATE in aggressive tumors or whether a sequential approach would offer better or similar long-term outcomes while preserving patients’ quality of life.

• © 2025 by the Society of Nuclear Medicine and Molecular Imaging.

• Received for publication April 5, 2025.
• Accepted for publication April 10, 2025.