COPEC trial: Early determination of pathological tumor response to neoadjuvant chemotherapy in low/intermediate risk stage II/II rectal cancer—A multicenter, non-inferiority phase III randomized trial.

3535 Background: Multiple large-scale prospective studies have confirmed that neoadjuvant chemotherapy (NCT) alone can achieve optimal distant and local control in locally advanced rectal cancers (LARC) without high risks. However, due to the potentially lower overall response rate compared to chemo-radiotherapy, it is rational to discontinue ineffective NCT in chemo-resistant patients. In our phase II study, we applied 4 cycles of Capox in LARC patients with low to intermediate risks, observing a considerable patho-clinical response rate and an accuracy of 0.89 in predicting non-responders using MRI features after two cycles of Capox. To determine the optimal number of NCT cycles and prevent unnecessary prolonged treatment, we conducted this phase III trial to assess the non-inferiority of two cycles of NCT compared to four cycles with respect to the final pathological tumor response grade (pTRG) of 3. Methods: This multicenter, non-inferiority, phase III randomized controlled trial was conducted at 14 centers across China. Eligible patients with low- to intermediate-risk stage II/III rectal cancer were randomized to receive either 2 or 4 cycles of CAPOX, followed by total mesorectal excision (TME) surgery. The primary endpoint was the proportion of patients with a poor pathological response to NCT (pTRG 3). Secondary outcomes included the accuracy of MRI in predicting tumor response, treatment-related adverse events, and 3-year survival outcomes. Results: From August 6, 2021, to May 27, 2024, a total of 573 patients were enrolled. Ultimately, 527 patients (2-cycle group, 266 vs. 4-cycle group, 261) were included in the primary analysis. The pTRG 3 rate in the 2-cycle group (27.8%, 74/266) was non-inferior to that in the 4-cycle group (26.4%, 69/261, p = 0.722). Better lymph node response was observed in the 4-cycle group (pN negative: 83.1%, 217/261 vs. 72.5%, 193/266, p = 0.011). The incidence of major adverse events (grade ≥3, according to CTCAE 5.0) was comparable between the two groups (37.9% vs. 44.8%, p = 0.094). A tumor longitudinal length reduction rate (TLLR) of less than 30% on MRI predicted pathological poor responders with a high positive predictive value of 0.918 after two cycles of NCT in the two-cycle group, 0.864 after two cycles of NCT in the four-cycle group, and 0.841 after four cycles of NCT in the four-cycle group. Conclusions: Four cycles of NCT do not result in a greater reduction in poor pathological response compared to two cycles, highlighting the importance of early response assessment. MRI evaluation of tumor response after 2 cycles predict the final pathological results with considerable accuracy. These findings lay the groundwork for future studies exploring response-guided treatment approaches in rectal cancer. Clinical trial information: NCT04922853 .