Reported by Prof Marc Van den Eynde, Saint-Luc hospital, Brussels
Two investigations were presented concerning RAS-wildtype unresectable metastatic colon cancer, employing FOLFOXIRI treatment paired with the antibody therapy cetuximab.
The first, TRICE, was a randomized clinical trial comparing the chemotherapy backbone of either FOLFOXIRI or FOLFOX, both in combination with cetuximab, in a first-line setting. The primary endpoint ORS was consistent with prior findings, FOLFOXIRI did not enhance ORS. This suggests that, for these RAS-wildtype patients, doublet therapy seems to be sufficient when selected according to their primary tumour and RAS-wildtype status.
The PANIRINOX-UCGI28 study examined the same question using panitumumab. Genotyping patients’ RAS/BRAF V600E status using ctDNA revealed a similar outcome. While triplet therapy demonstrated clinical response rates, it didn’t surpass the efficacy of doublet therapy. Moreover, it exhibited higher toxicity, leading to severe side effects like neutropenia and haematological toxicity. Both studies indicated no change in overall survival for patients.
In the NICHE-3 study, neoadjuvant nivolumab with relatlimab was investigated in locally advanced MMR-deficient nonmetastatic colon cancer. Though employing different treatment doses, schedules, and surgery timings than NICHE-1 and NICHE-2, NICHE-3 showed a 100% pathological response rate, with a complete pathological response rate in 79% of patients. These preliminary data are promising, with a manageable safety profile.
Additionally, the KEYNOTE-177 study, comparing pembrolizumab with chemotherapy in the first-line metastatic setting, offered an update. The long-term follow-up of more than 5 years revealed encouraging results, with a median OS of over 6.5 years, unprecedented in metastatic colorectal cancer. This provides hope for immunotherapy in colon cancer, especially as a first-line treatment, suggesting the potential for a cure in more than half of patients.
Lastly, the GALAXY trial explored the prognostic significance of (ct)DNA as a biomarker in resected CRC patients. The study demonstrated the predictive power of (ct)DNA; negative postoperative (ct)DNA outcomes correlated with significantly higher DFS. Therefore, patients positive for (ct)DNA but not (ct)DNA-negative individuals benefited from adjuvant chemotherapy post-resection. Additionally, (ct)DNA’s predictive ability regarding adjuvant chemotherapy showed promise. Patients positive for (ct)DNA benefited from adjuvant chemotherapy, making patient selection based on this parameter highly relevant. Notably, the study revealed that regardless of risk, (ct)DNA-positive patients benefited from a 6-month chemotherapy regimen compared to a 3-month adjuvant treatment, challenging previous assumptions.
It is essential to note that these results are observational, given the lack of intervention in the GALAXY trial. However, the substantial sample size, comprising over 2000 patients in various stages (from stage 2 to 4), renders these findings highly significant. The study offers a crucial observation on the added value of (ct)DNA in tailoring treatment strategies for colorectal cancer patients.
References
Mazard T. – Panitumumab (P) + FOLFIRINOX or mFOLFOX6 in unresectable metastatic colorectal cancer (mCRC) patients (pts) with RAS/BRAF wild-type (WT) tumor status from circulating DNA (cirDNA). First results of the randomised phase II PANIRINOX-UCGI28 study. ESMO2023 – LBA30
Chen G. – Cetuximab plus FOLFOXIRI versus cetuximab plus FOLFOX in RAS wild-type patients with initially unresectable colorectal liver metastases: The TRICE randomized clinical trial. ESMO2023 – 554MO
Sunakawa Y. – Modified (m)-FOLFOXIRI plus cetuximab treatment and predictive clinical factors for RAS/BRAF wild-type and left-sided metastatic colorectal cancer (mCRC): the DEEPER trial (JACCRO CC-13). ESMO2023 – 555MO
Verschoor Y. – Neoadjuvant nivolumab plus relatlimab (anti-LAG3) in locally advanced MMR-deficient colon cancers: the NICHE-3 study. ESMO2023 – LBA31
Wang F. – A phase II clinical trial of sintilimab plus chidamide combined with or without bevacizumab in patients with MSS/pMMR metastatic colorectal cancer. ESMO2023 – 556MO
Shiu K.-K. – Pembrolizumab versus chemotherapy in microsatellite instability-high (MSI-H)/mismatch repair-deficient (dMMR) metastatic colorectal cancer (mCRC): 5-year follow-up of the randomized phase 3 KEYNOTE-177 study. ESMO2023 – LBA32
Coutzac C. – Phase II trial evaluating the efficacy of pembrolizumab combined with vorinostat in patients with recurrent and/or metastatic anal squamous cell carcinoma – subgroup analysis of the PEVOsq basket trial. ESMO2023 – 557MO
Nakamura Y. – Circulating tumor (ct)DNA as a prognostic biomarker in patients (pts) with resected colorectal cancer (CRC): an updated 24 months (mos) disease free survival (DFS) analysis from GALAXY study (CIRCULATE-Japan). ESMO2023 – 558MO
Ciardiello D. – Rechallenge with EGFR inhibitors in ctDNA RAS/BRAF wild type refractory metastatic colorectal cancer: individual patients’ data pooled analysis from 4 phase II trials. ESMO2023 – 559MO
García Alfonso P. – Maintenance with 5FU/LV-Aflibercept after induction with FOLFIRI-Aflibercept vs FOLFIRI-Aflibercept until progression in older patients (pts) in 2nd line metastatic colorectal cancer (mCRC): the randomized AFEMA trial. ESMO2023 – 560MO
With the educational support of:
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