P0253 - Comparative Efficacy and Safety of KRAS G12C-Targeted Therapies in Metastatic Colorectal Cancer: A Systematic Review and Network Meta-Analysis

Rakhshanda Khan, MBBS¹, Harshawardhan Dhanraj Ramteke, MBBS², Ashesh Das, MBBS³, Srikar P. Chilla, MD, MScPH⁴, Prakhar Bajpai, MBBS⁵, Hakim Wazir, MBBS⁶, Sri Mani Krishna Satvik Matta, MBBS⁷, Valency Pateliya, MBBS⁸, Urwa Nabilah, MBBS⁹, Priyal Bhanushali, MBBS¹⁰, Yusra Tazeen, MBBS¹¹, Sonam Dhall, MBBS¹², Akhil Tomy, MBBS¹³, Preeti —, MBBS¹⁴, Zoha M. Khan, MBBS¹⁵, Aditi Tyagi, MBBS¹⁶, Syeda Hafsa Noor-Ain, MBBS¹⁵, Ivin Thomas. Jolly, MBBBS², Rachit Agrawal, MBBS, MD¹⁷, Kapil Raut, DM, MD, MBBS¹⁸, Manish Madanlal. Juneja, DM, MD, MBBS¹⁹
1Ayaan institute of medical sciences, Moinabad, Telangana, India; 2Anhui Medical University, Hefei, Hefei, Anhui, China; 3KPC Medical College and Hospital , Kolkata, India, Kolkata, West Bengal, India; 4American International Medical University, Hyderabad, Telangana, India; 5Jawaharlal Nehru Medical College, Belagavi, India, Belagavi, Karnataka, India; 6Gajju Khan Medical College,Swabi Pakistan Medicine department, Shahmansor, Swabi, North-West Frontier, Pakistan; 7Siddhartha Medical College Vijayawada, Vijayawada, Andhra Pradesh, India; 8Pramukhswami Medical College, Himmatnagar, Gujarat, India; 9Shadan Institute of Medical Sciences, Hyderabad, Telangana, India; 10Jaslok Hospital and Research Center, Mumbai, Maharashtra, India; 11Ayaan Institute of medical sciences, Moinabad, Telangana, India; 12Dayanand Medical College and Hospital, Edison, NJ; 13Betsi Cadwaladr University Health Board, Rhyl, Wales, United Kingdom; 14V.N Karazin Kharkiv National University, Yamuna Nagar, Haryana, India; 15Ayaan Institute of Medical Sciences, Hyderabad, Telangana, India; 16V N karazin kharkiv national university, Yamuna Nagar, Haryana, India; 17saraswati kidney care center, Nagpur, Maharashtra, India; 18HCG cancer center, Nagpur, Maharashtra, India; 19Rhythm Heart and Critical Care, Nagpur, Nagpur, Maharashtra, India

Introduction: KRAS G12C mutations, found in 3-5% of metastatic colorectal cancer cases, drive aggressive disease with limited treatment options. Recent advances in covalent inhibitors have enabled selective targeting of KRAS G12C, marking a significant shift in precision oncology and offering new treatment options for these patients.

Methods: A systematic search of five databases identified relevant Phase I to Phase III trials, with Screening performed using Covidence. Network meta-analysis was conducted using the Netmeta package in R, and forest plots and additional analyses were generated in Stata 18.0. Risk of bias was assessed with the RoB-ME tool.

Results: A total of 1,923 records were identified, and after removing duplicates and screening, 14 studies met the inclusion criteria for analysis. A total of 574 patients were included across multiple treatment arms, comprising Sotorasib 960 mg (62), Sotorasib 960 mg + Panitumumab (93), Adagrasib 1200 mg (44), Divarasib + Cetuximab (29), Olomarasib + Cetuximab (49), Sotorasib 960 mg + Panitumumab + FOLFIRI (31), Adagrasib 1200 mg + Cetuximab (94), Sotorasib alone (42), Sotorasib + Panitumumab (39), Adagrasib alone (4), Divarasib alone (55), and Olomarasib alone (32) treatment cohorts. The highest mean ORR was observed in the Sotorasib 960mg + Panitumumab + FOLFIRI group (58.1%, 95% CI: 51.7%–64.5%), while the lowest mean ORR was consistently seen in the Placebo groups (1%, 95% CI: not estimable due to sample size). According to SUCRA,the treatment regimen of Sotorasib 960mg combined with Panitumumab and FOLFIRI demonstrated the highest ranking in efficacy, while Adagrasib 1200mg in combination with Cetuximab was ranked lowest among the evaluated interventions. This enhanced efficacy, however, corresponded with an increased risk of treatment-related adverse events (TRAE), reflected by a risk ratio (RR) of 1.13 (95% CI: 0.95 to 1.73), with diarrhea and nausea exhibiting notably elevated risks—RRs of 3.42 (95% CI: 2.25 to 4.59) and 3.01 (95% CI: 2.04 to 3.99), respectively. Quality of life (QOL) was significantly improved in patients, and risk of bias assessment using the ROB-ME tool indicated a moderate to low risk of bias across the included studies.

Discussion: This analysis highlights the superior efficacy of Sotorasib 960mg with Panitumumab and FOLFIRI in metastatic colorectal cancer, despite increased risks of diarrhea and nausea. Significant QOL improvements and a moderate to low risk of bias support the regimen's therapeutic potential.


Figure: Summary of the KRAS G12C-Targeted Therapies in Metastatic Colorectal Cancer: A Network Meta-Analysis

Disclosures:
Rakhshanda Khan indicated no relevant financial relationships.
Harshawardhan Dhanraj Ramteke indicated no relevant financial relationships.
Ashesh Das indicated no relevant financial relationships.
Srikar Chilla indicated no relevant financial relationships.
Prakhar Bajpai indicated no relevant financial relationships.
Hakim Wazir indicated no relevant financial relationships.
Sri Mani Krishna Satvik Matta indicated no relevant financial relationships.
Valency Pateliya indicated no relevant financial relationships.
Urwa Nabilah indicated no relevant financial relationships.
Priyal Bhanushali indicated no relevant financial relationships.
Yusra Tazeen indicated no relevant financial relationships.
Sonam Dhall indicated no relevant financial relationships.
Akhil Tomy indicated no relevant financial relationships.
Preeti — indicated no relevant financial relationships.
Zoha Khan indicated no relevant financial relationships.
Aditi Tyagi indicated no relevant financial relationships.
Syeda Hafsa Noor-Ain indicated no relevant financial relationships.
Ivin Jolly indicated no relevant financial relationships.
Rachit Agrawal indicated no relevant financial relationships.
Kapil Raut indicated no relevant financial relationships.
Manish Juneja indicated no relevant financial relationships.

Rakhshanda Khan, MBBS¹, Harshawardhan Dhanraj Ramteke, MBBS², Ashesh Das, MBBS³, Srikar P. Chilla, MD, MScPH⁴, Prakhar Bajpai, MBBS⁵, Hakim Wazir, MBBS⁶, Sri Mani Krishna Satvik Matta, MBBS⁷, Valency Pateliya, MBBS⁸, Urwa Nabilah, MBBS⁹, Priyal Bhanushali, MBBS¹⁰, Yusra Tazeen, MBBS¹¹, Sonam Dhall, MBBS¹², Akhil Tomy, MBBS¹³, Preeti —, MBBS¹⁴, Zoha M. Khan, MBBS¹⁵, Aditi Tyagi, MBBS¹⁶, Syeda Hafsa Noor-Ain, MBBS¹⁵, Ivin Thomas. Jolly, MBBBS², Rachit Agrawal, MBBS, MD¹⁷, Kapil Raut, DM, MD, MBBS¹⁸, Manish Madanlal. Juneja, DM, MD, MBBS¹⁹. P0253 - Comparative Efficacy and Safety of KRAS G12C-Targeted Therapies in Metastatic Colorectal Cancer: A Systematic Review and Network Meta-Analysis, ACG 2025 Annual Scientific Meeting Abstracts. Phoenix, AZ: American College of Gastroenterology.