RAS wild-type + BRAF wild-type

The LIBImAb Study is a phase III, randomized, openlabel, comparative, multi-center trial to assess the superiority in terms of efficacy of bevacizumab versus cetuximab in combination with FOLFIRI in mCRC pts, RAS/BRAFwt on tumor tissue and RAS/BRAF mutant (RAS/BRAFmut) at liquid biopsy... These data indicate the feasibility of cfDNA-based prospective enrolment in an interventional trial using a test with a rapid TAT for screening of RAS/ BRAF status in plasma. Our preliminary findings also suggest that ctDNA testing might better recapitulate the tumor heterogeneity of mCRC pts thus complementing tissue genomic profiling.

In this single-center, prospective, randomized controlled trial, we randomly assigned (1 : 1) patients with locally advanced rectal cancer with wild-type RAS/BRAF gene to two groups: 5 cycles of modified leucovorin calcium (folinic acid), fluorouracil, and oxaliplatin combination regimen (modified FOLFOX6, mFOLFOX6) concurrent with 25 times radiotherapy or 5 cycles of mFOLFOX6 plus cetuximab, all with subsequent total mesorectal excision (TME) resection and adjuvant chemotherapy. Additionally, lower rates of preventive enterostomy and low anterior resection syndrome were shown in the mFOLFOX6-Cet group compared to the mFOLFOX6-RT group. The neoadjuvant treatment strategy of mFOLFOX6 with cetuximab is feasible and promising for patients with locally advanced rectal cancer, even superior to mFOLFOX6 with radiotherapy.

P1/2, N=52, Completed, TyrNovo Ltd. | Active, not recruiting --> Completed | N=110 --> 52

P1/2, N=110, Active, not recruiting, TyrNovo Ltd. | Trial completion date: Sep 2024 --> Jun 2024

P1, N=26, Completed, City of Hope Medical Center | Active, not recruiting --> Completed | Trial completion date: Dec 2023 --> Jul 2023 | Trial primary completion date: Dec 2023 --> Jul 2023

Therefore, clinical relevance exists for analyses of MSI and MSI-H-associated genomic alterations in malignancy. In this article, we provide an update on MSI-driven carcinogenesis, with an emphasis on unique landscapes of diagnostic and immunotherapeutic strategies.

P2, N=150, Recruiting, West China Hospital | Trial completion date: Jun 2024 --> Jun 2026 | Trial primary completion date: Jun 2024 --> Jun 2025

P1/2, N=110, Active, not recruiting, TyrNovo Ltd. | Recruiting --> Active, not recruiting

Although we suggested chemotherapy due to the unresectable recurrence of colorectal cancer, she preferred to receive supportive care instead. Three months after the recurrence was diagnosed, CEA increased to 248.4 ng/mL, and CT showed enlargement of the axillary lesion and a new lesion in the hilum of the lung.

P1/2, N=110, Recruiting, TyrNovo Ltd.

RAS/BRAF mutations negatively impact primary tumor response rates after TNT in patients with advanced rectal cancer. Large-scale national studies are needed to determine whether RAS/BRAF status could be used to select optimal oncologic therapy in rectal cancer patients.

Sponsored by NCI, NCI Background: Cetuximab (CTX) and Panitumumab (PMB) therapies directed at EGFR have been restricted to left-sided CRC harboring wild-type KRAS (KRASWT), limiting their utility. Our data suggest that CTX-S may predict longer survival on EGFRi, surprisingly independent of RAS/BRAF mutation status as well as tumor sidedness. Patients with high CTX-S had increased prevalence of CMS2 and harbored more APC and TP53 mutations. A strong EGFRi biomarker would likely expand the utility of EGFRi to right-sided tumors and possibly to RASMUT tumors.

Sponsored by NCI, NCI Background: Although, EGFRi including Cetuximab (CTX) and Panitumumab (PMB) is restricted to KRAS wild-type (KRASWT) tumors, ~50% of patients still fail to respond to therapy. Our data suggests that the simple application of a high-utility mutational biomarker (APC), may increase the eligibility for successful EGFRi therapy in a substantial subpopulation of RAS/BRAF mt patients as well as right-sided CRC, potentially altering the standard of care. Further validation of this biomarker in a prospective clinical trial is warranted. >

HAI oxaliplatin plus systemic 5-fluorouracil and cetuximab appears highly effective in the frontline treatment of patients with unresectable CRLM and should be investigated further.

In BRAF-mutant CRC cells, OBP-301 and OBP-702 suppressed the expression of EGFR, MEK, ERK, and AKT proteins, whereas mTOR expression was suppressed only by OBP-702. Our results suggest that p53-armed oncolytic virotherapy is a viable therapeutic option for treating KRAS/BRAF-mutant CRC cells via induction of autophagy and apoptosis.

P1/2, N=110, Recruiting, TyrNovo Ltd. | N=75 --> 110 | Trial completion date: Sep 2023 --> Sep 2024 | Trial primary completion date: Jun 2023 --> Jun 2024

P2, N=80, Not yet recruiting, Peking University Cancer Hospital & Institute

Mechanistically, co-treatment inhibited FOXO3a phosphorylation and degradation and activated the FOXO3a/AMPKα/pBeclin1 and FOXO3a/PUMA pathways, leading to the promotion of ferroptosis, autophagy, and apoptosis in DLD-1 (KRAS), HT29 (BRAF), and Caco-2-CR cells. In conclusion, our findings suggest that co-treatment with 3-BP and cetuximab could be a promising strategy to overcome cetuximab resistance in human CRC.

P1, N=26, Active, not recruiting, City of Hope Medical Center | Trial completion date: Feb 2023 --> Dec 2023 | Trial primary completion date: Feb 2023 --> Dec 2023

P2, N=7, Terminated, Sichuan Baili Pharmaceutical Co., Ltd. | N=120 --> 7 | Trial completion date: Sep 2023 --> Jun 2022 | Recruiting --> Terminated | Trial primary completion date: Sep 2023 --> Jun 2022; Company research strategy adjustment

SCT200 showed favorable safety, PK profile, and preliminary efficacy for patients with wild-type KRAS/NRAS/BRAF mCRC.

P1, N=26, Active, not recruiting, City of Hope Medical Center | Trial completion date: Sep 2022 --> Feb 2023 | Trial primary completion date: Sep 2022 --> Feb 2023

There were significant differences in resectability, conversion and resection/LAT rates according to RAS and BRAF status. OS was also significantly longer for RAS and BRAFwt versus either mutant. Patients only receiving systemic therapy had poorer long-term survival, with variation according to molecular status.

Treatment with Sorafenib and UO126 inhibited proliferation of Ba/F3-SOX5-RAF1 cells in the absence of IL3 but not the PLX 4720, a specific inhibitor of BRAF. These results indicate that SOX5-RAF1, a driver event for CMN development, has oncogenic capacity. Thus, sequencing of CMN transcriptomes may lead to identification of this druggable fusion and to interfere with the progression towards melanoma.

STRATEGIC-1 is the first randomized phase III study comparing multi-line standard treatment strategies in patients with KRAS/NRAS/BRAF wild-type mCRC. This study did not meet its primary endpoint of DDC. The treatment strategy starting with FOLFIRI-cetuximab followed by mFOLFOX6-bevacizumab led to higher response rates and to a trend for better median OS exceeding 3 years.

P2, N=151, Completed, National Cancer Institute, Naples | Active, not recruiting --> Completed | Trial completion date: Dec 2021 --> Apr 2022

To sum up, our findings point to the combined blockage of IL-1R and EGFR as a promising therapeutical approach to restore sensitivity to EGFR-targeting monoclonal antibodies.

ERAS-007 demonstrated monotherapy activity and combination benefit in cell-based assays as well as superior combination efficacy in vivo relative to respective monotherapy control arms.In summary, ERAS-007 demonstrates promising preclinical activity across a wide range of RAS/MAPK pathway-driven CRC models both as a monotherapy and in combination that support further exploration in the clinic. Accordingly, ERAS-007 combinations with encorafenib + cetuximab in BRAFV600E CRC and with palbociclib in KRASmut CRC are currently being evaluated in the HERKULES-3 phase 1b/2 master protocol (NCT05039177).

P1, N=26, Active, not recruiting, City of Hope Medical Center | Trial completion date: Sep 2021 --> Sep 2022 | Trial primary completion date: Sep 2021 --> Sep 2022