Re-treatment with panitumumab followed by regorafenib versus the reverse sequence in chemorefractory metastatic colorectal cancer patients with RAS and BRAF wild-type circulating tumor DNA: the PARERE study by GONO.

patients_and_methods

PARERE (NCT04787341) is an open-label, multicenter, randomized phase II trial investigating the optimal sequencing of panitumumab and regorafenib in chemorefractory RAS and BRAF wt mCRC patients, who previously derived benefit from first-line anti-EGFR-containing regimens, then received at least one intervening anti-EGFR-free line of treatment, and were prospectively selected for the absence of RAS and BRAF mutations in their ctDNA.

PARERE（NCT04787341）是一项开放标签、多中心、随机的II期临床试验，旨在研究在化学耐药的RAS和BRAF野生型（wt）mCRC患者中，最佳的帕尼单抗和瑞戈非尼的序贯治疗方案。这些患者之前从一线抗EGFR治疗方案中获益，随后接受了至少一种不含抗EGFR的治疗方案，并且前瞻性地被选为ctDNA中没有RAS和BRAF突变。

Eligible patients were randomly assigned 1 : 1 to receive anti-EGFR re-treatment with panitumumab followed by regorafenib after progression (arm A) versus the reverse sequence (arm B).

符合条件的患者按1:1的比例随机分配，接受panitumumab抗EGFR再治疗，随后在进展后接受regorafenib治疗（A组）与相反的顺序（B组）。

The primary endpoint was overall survival(OS).

主要终点是总生存（OS）。

Results

Between December 2020 and December 2024, 428 patients underwent molecular screening, and 213 with RAS/BRAF ctDNA wt were randomized (arm A/B = 106/107).

在2020年12月至2024年12月期间，共有428名患者接受了分子筛查，其中213名RAS/BRAF ctDNA wt患者被随机分配到两个治疗组（A组/B组=106/107）。

At a median follow-up of 31.9 months, no difference in terms of OS was observed between treatment arms, with a median OS of 11.7 and 11.6 months in arms B and A, respectively (hazard ratio1.13, 85% confidence interval0.90-1.41, P = 0.441).

在中位随访31.9个月时，两组治疗在总生存（OS）方面没有观察到差异，B组和A组的中位总生存期分别为11.7个月和11.6个月（风险比1.13，95%置信区间0.90-1.41，P = 0.441）。

However, re-treatment with panitumumab was associated with higher objective response rate(ORR; first ORR: 16% versus 2%, P = 0.003; second ORR: 18% versus 0%, P = 0.013) and disease control rate (DCR; first DCR: 61% versus 36%, P < 0.001; second DCR: 62% versus 38%, P = 0.003), and longer progression-free survival(PFS; first PFS: 4.2 versus 2.4 months, P = 0.103; second PFS: 3.9 versus 2.7 months, P = 0.019) than regorafenib, regardless of the sequence of the study treatments.

然而，与瑞戈非尼相比，帕尼单抗的再次治疗与更高的客观缓解率（ORR；首次ORR：16%对比2%，P=0.003；第二次ORR：18%对比0%，P=0.013）和疾病控制率（DCR；首次DCR：61%对比36%，P<0.001；第二次DCR：62%对比38%，P=0.003）相关，且无进展生存期（PFS；首次PFS：4.2个月对比2.4个月，P=0.103；第二次PFS：3.9个月对比2.7个月，P=0.019）更长，无论研究治疗的顺序如何。

Conclusions

Anti-EGFR re-treatment should be regarded as an option in the continuum of care of chemorefractory mCRC patients with RAS and BRAF wt tumors, with no alterations of acquired resistance in their ctDNA.

对于RAS和BRAF野生型肿瘤的化疗耐药性转移性结直肠癌（mCRC）患者，如果他们的循环肿瘤DNA（ctDNA）中未出现获得性耐药的改变，应将抗表皮生长因子受体（EGFR）的再次治疗视为他们治疗连续性中的一个选项。