What are the treatment options for Ras-related cancer?

Treatment Options for RAS-Related Cancer

For RAS-related cancers, treatment should be tailored based on the specific RAS mutation type, tumor location, and previous treatment history, with targeted therapies combined with chemotherapy regimens offering the best outcomes for morbidity and mortality.

Treatment Approach Based on RAS Mutation Status

For RAS Wild-Type Tumors

• For left-sided RAS wild-type tumors, a cytotoxic doublet plus an EGFR antibody (cetuximab or panitumumab) is the preferred first-line treatment option 1
• For right-sided RAS wild-type tumors, a cytotoxic triplet plus bevacizumab should be the treatment of choice, although a cytotoxic doublet plus an EGFR antibody can also be considered 1
• For BRAF V600E-mutated tumors, encorafenib-cetuximab is recommended as the best option in second and third line 1

For RAS Mutant Tumors

• A cytotoxic doublet plus bevacizumab is the preferred first-line option 1
• A cytotoxic triplet plus bevacizumab may be an alternative for selected, very fit and motivated patients 1
• Direct RAS inhibitors are under development but have not yet achieved widespread clinical success outside of specific mutations like KRAS G12C 2, 3

Treatment Strategy Based on Disease Presentation

For Potentially Resectable Disease (Conversion Therapy)

• The most active "induction" chemotherapy should be selected upfront 1
• Patients should be reevaluated every 2 months to ensure they are not overtreated 1
• If there is evidence of tumor shrinkage after 2 months, patients should be considered for potentially curative surgery 1
• If there is insufficient response after 4 months, changing the cytotoxic doublet is suggested to retain the chance of resection 1

For Aggressive Disease Requiring Cytoreduction

• Treatment should not be changed in patients without tumor progression and not suffering from major toxicity 1
• Reevaluation should occur every 2 months 1

For Disease Control as the Goal

• For RAS mutant or right-sided RAS wild-type disease, a cytotoxic doublet in combination with bevacizumab is recommended 1
• For left-sided RAS wild-type tumors, a cytotoxic doublet plus an EGFR antibody should be the treatment of choice 1
• Reevaluation should occur every 2-3 months 1
• In patients with good response or disease control, active maintenance therapy should be considered 1
• A fluoropyrimidine plus bevacizumab is the preferred maintenance option 1

Second-Line Treatment Options

• In patients treated with first-line oxaliplatin-based therapy, second-line treatment with irinotecan-based therapy or monotherapy is recommended 1
• For patients previously treated with irinotecan-based therapy, oxaliplatin-based treatment (FOLFOX or CAPOX) is recommended in second line 1
• In RAS wild-type patients not previously treated with an anti-EGFR antibody, treatment with chemotherapy (FOLFIRI or irinotecan) and cetuximab or panitumumab could be considered for left-sided colon tumors 1
• For right-sided tumors, second-line therapy with an anti-angiogenic combined with chemotherapy is recommended 1
• A second-line treatment with an antiangiogenic (bevacizumab, aflibercept, or ramucirumab) combined with chemotherapy should be used, regardless of whether the first-line treatment included bevacizumab 1

Third-Line and Beyond Treatment Options

• Reintroduction of the initial induction therapy can be considered after second-line therapy 1
• Regorafenib is recommended in patients pre-treated with fluoropyrimidines, oxaliplatin, irinotecan and biologics 1
• Trifluridine-tipiracil is recommended in patients pre-treated with fluoropyrimidines, oxaliplatin, irinotecan and biologics 1
• In RAS wild-type and BRAF wild-type patients not previously treated with EGFR antibodies, cetuximab and panitumumab are recommended as single agents 1
• In irinotecan-refractory patients, cetuximab-irinotecan is recommended over cetuximab alone 1

Special Considerations for Specific Molecular Subtypes

For BRAF V600E-Mutated Tumors

• Encorafenib-cetuximab is recommended as the best option in second and third line 1
• Vemurafenib + Irinotecan + Cetuximab or Dabrafenib + Cetuximab ± Trametinib can be considered for RAS wild-type/BRAF V600E mutation 1

For dMMR/MSI-H Tumors

• For dMMR/MSI-H tumors progressing after first-line chemotherapy, ipilimumab-nivolumab is recommended 1
• Pembrolizumab, Nivolumab, Nivolumab + Ipilimumab, Envafolimab, Serplulimab, or Tislelizumab can be considered 1

For HER2-Amplified Tumors

• In HER2-positive patients with metastatic colorectal cancer, treatment with HER2 dual blockade is optionally recommended, especially in RAS wild-type tumors 1
• Trastuzumab + Pertuzumab or Trastuzumab + Lapatinib can be considered 1

Future Directions in RAS-Targeted Therapy

• Direct inhibition of mutant RAS through allele-specific inhibitors currently provides the best therapeutic approach 2
• Combination strategies that target multiple nodes within the RAS pathway or co-target RAS and other therapeutic vulnerabilities are being investigated 3
• Vertical strategies targeting multiple nodes within the RAS pathway to achieve deeper suppression are being investigated 3
• The complexity of the RAS-signaling pathway and differences between various RAS isoforms may affect the choice of therapeutic approach 4, 5
• Multi-target drug combinations addressing the crosstalk between RAS pathways are becoming a research hotspot 6