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The New England Journal of Medicine Dec 2023G12C is a mutation that occurs in approximately 3 to 4% of patients with metastatic colorectal cancer. Monotherapy with KRAS G12C inhibitors has yielded only modest... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
G12C is a mutation that occurs in approximately 3 to 4% of patients with metastatic colorectal cancer. Monotherapy with KRAS G12C inhibitors has yielded only modest efficacy. Combining the KRAS G12C inhibitor sotorasib with panitumumab, an epidermal growth factor receptor (EGFR) inhibitor, may be an effective strategy.
METHODS
In this phase 3, multicenter, open-label, randomized trial, we assigned patients with chemorefractory metastatic colorectal cancer with mutated G12C who had not received previous treatment with a KRAS G12C inhibitor to receive sotorasib at a dose of 960 mg once daily plus panitumumab (53 patients), sotorasib at a dose of 240 mg once daily plus panitumumab (53 patients), or the investigator's choice of trifluridine-tipiracil or regorafenib (standard care; 54 patients). The primary end point was progression-free survival as assessed by blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Key secondary end points were overall survival and objective response.
RESULTS
After a median follow-up of 7.8 months (range, 0.1 to 13.9), the median progression-free survival was 5.6 months (95% confidence interval [CI], 4.2 to 6.3) and 3.9 months (95% CI, 3.7 to 5.8) in the 960-mg sotorasib-panitumumab and 240-mg sotorasib-panitumumab groups, respectively, as compared with 2.2 months (95% CI, 1.9 to 3.9) in the standard-care group. The hazard ratio for disease progression or death in the 960-mg sotorasib-panitumumab group as compared with the standard-care group was 0.49 (95% CI, 0.30 to 0.80; P = 0.006), and the hazard ratio in the 240-mg sotorasib-panitumumab group was 0.58 (95% CI, 0.36 to 0.93; P = 0.03). Overall survival data are maturing. The objective response was 26.4% (95% CI, 15.3 to 40.3), 5.7% (95% CI, 1.2 to 15.7), and 0% (95% CI, 0.0 to 6.6) in the 960-mg sotorasib-panitumumab, 240-mg sotorasib-panitumumab, and standard-care groups, respectively. Treatment-related adverse events of grade 3 or higher occurred in 35.8%, 30.2%, and 43.1% of patients, respectively. Skin-related toxic effects and hypomagnesemia were the most common adverse events observed with sotorasib-panitumumab.
CONCLUSIONS
In this phase 3 trial of a KRAS G12C inhibitor plus an EGFR inhibitor in patients with chemorefractory metastatic colorectal cancer, both doses of sotorasib in combination with panitumumab resulted in longer progression-free survival than standard treatment. Toxic effects were as expected for either agent alone and resulted in few discontinuations of treatment. (Funded by Amgen; CodeBreaK 300 ClinicalTrials.gov number, NCT05198934.).
Topics: Humans; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; ErbB Receptors; Immune Checkpoint Inhibitors; Mutation; Panitumumab; Proto-Oncogene Proteins p21(ras); Trifluridine
PubMed: 37870968
DOI: 10.1056/NEJMoa2308795 -
Journal of Clinical Oncology : Official... Dec 2023To verify whether both doublet chemotherapy with a modified schedule of fluorouracil, leucovorin, and oxaliplatin (mFOLFOX) and monochemotherapy with fluorouracil plus... (Randomized Controlled Trial)
Randomized Controlled Trial
Initial Panitumumab Plus Fluorouracil, Leucovorin, and Oxaliplatin or Plus Fluorouracil and Leucovorin in Elderly Patients With RAS and BRAF Wild-Type Metastatic Colorectal Cancer: The PANDA Trial by the GONO Foundation.
PURPOSE
To verify whether both doublet chemotherapy with a modified schedule of fluorouracil, leucovorin, and oxaliplatin (mFOLFOX) and monochemotherapy with fluorouracil plus leucovorin (5-FU + LV) achieve satisfactory efficacy when both regimens are combined with panitumumab (PAN) as initial treatment of elderly patients with / wild-type metastatic colorectal cancer (mCRC).
PATIENTS AND METHODS
PANDA (ClinicalTrials.gov identifier: NCT02904031) was an open-label, randomized phase II noncomparative trial in previously untreated patients age 70 years and older with unresectable / wild-type mCRC. Patients were randomly assigned 1:1 to mFOLFOX + PAN (arm A) or 5-FU + LV + PAN (arm B) for up to 12 cycles, followed by PAN maintenance. The primary end point was progression-free survival (PFS). In each arm, assuming a null hypothesis of median PFS time 6 months and target PFS ≥9.65, 90 patients per arm were needed to achieve 90% power and 5% type I error (one-sided Brookmeyer-Crowley test).
RESULTS
Between July 2016 and April 2019, 91 patients were randomly assigned to arm A and 92 to arm B. At a median follow-up of 50.0 months (IQR, 45.6-56.4), median PFS was 9.6 and 9.0 months for arm A and B, respectively ( < .001 in each arm). Overall response rate was 69% and 52%, whereas median overall survival was 23.5 and 22.0 months in arm A and B, respectively. The overall rate of grade >2 chemotherapy-related adverse events was 60% and 37%, respectively. Baseline G8 and Chemotherapy Risk Assessment Scale for High-Age Patients scores were prognostic, but they were not associated with efficacy and safety of the two arms.
CONCLUSION
Both mFOLFOX and 5-FU + LV + PAN are reasonable options as initial therapy of elderly patients with / wild-type mCRC. 5-FU + LV + PAN is associated with a better safety profile.
Topics: Humans; Aged; Panitumumab; Oxaliplatin; Proto-Oncogene Proteins B-raf; Colorectal Neoplasms; Leucovorin; Fluorouracil; Colonic Neoplasms; Rectal Neoplasms; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37535876
DOI: 10.1200/JCO.23.00506 -
Nature Medicine Jan 2024The current third-line (and beyond) treatment options for RAS-mutant metastatic colorectal cancer have yielded limited efficacy. At the time of study start, the...
The current third-line (and beyond) treatment options for RAS-mutant metastatic colorectal cancer have yielded limited efficacy. At the time of study start, the combination of sotorasib, a KRAS (Kirsten rat sarcoma viral oncogene homolog)-G12C inhibitor, and panitumumab, an epidermal growth factor receptor (EGFR) inhibitor, was hypothesized to overcome treatment-induced resistance. This phase 1b substudy of the CodeBreaK 101 master protocol evaluated sotorasib plus panitumumab in patients with chemotherapy-refractory KRAS-mutated metastatic colorectal cancer. Here, we report the results in a dose-exploration cohort and a dose-expansion cohort. Patients received sotorasib (960 mg, once daily) plus panitumumab (6 mg kg, once every 2 weeks). The primary endpoints were safety and tolerability. Secondary endpoints included efficacy and pharmacokinetics. Exploratory biomarkers at baseline were assessed. Forty-eight patients (dose-exploration cohort, n = 8; dose-expansion cohort, n = 40) were treated. Treatment-related adverse events of any grade and grade ≥3 occurred in 45 (94%) and 13 (27%) patients, respectively. In the dose-expansion cohort, the confirmed objective response rate was 30.0% (95% confidence interval (CI) 16.6%, 46.5%). Median progression-free survival was 5.7 months (95% CI 4.2, 7.7 months). Median overall survival was 15.2 months (95% CI 12.5 months, not estimable). Prevalent genomic coalterations included APC (84%), TP53 (74%), SMAD4 (33%), PIK3CA (28%) and EGFR (26%). Sotorasib-panitumumab demonstrated acceptable safety with promising efficacy in chemotherapy-refractory KRAS-mutated metastatic colorectal cancer. ClinicalTrials.gov identifier: NCT04185883 .
Topics: Humans; Panitumumab; Proto-Oncogene Proteins p21(ras); Antibodies, Monoclonal; Colorectal Neoplasms; ErbB Receptors; Mutation; Antineoplastic Combined Chemotherapy Protocols; Piperazines; Pyridines; Pyrimidines
PubMed: 38177853
DOI: 10.1038/s41591-023-02717-6 -
Cancer Discovery May 2024KRASG12C inhibitors, like sotorasib and adagrasib, potently and selectively inhibit KRASG12C through a covalent interaction with the mutant cysteine, driving clinical...
UNLABELLED
KRASG12C inhibitors, like sotorasib and adagrasib, potently and selectively inhibit KRASG12C through a covalent interaction with the mutant cysteine, driving clinical efficacy in KRASG12C tumors. Because amino acid sequences of the three main RAS isoforms-KRAS, NRAS, and HRAS-are highly similar, we hypothesized that some KRASG12C inhibitors might also target NRASG12C and/or HRASG12C, which are less common but critical oncogenic driver mutations in some tumors. Although some inhibitors, like adagrasib, were highly selective for KRASG12C, others also potently inhibited NRASG12C and/or HRASG12C. Notably, sotorasib was five-fold more potent against NRASG12C compared with KRASG12C or HRASG12C. Structural and reciprocal mutagenesis studies suggested that differences in isoform-specific binding are mediated by a single amino acid: Histidine-95 in KRAS (Leucine-95 in NRAS). A patient with NRASG12C colorectal cancer treated with sotorasib and the anti-EGFR antibody panitumumab achieved a marked tumor response, demonstrating that sotorasib can be clinically effective in NRASG12C-mutated tumors.
SIGNIFICANCE
These studies demonstrate that certain KRASG12C inhibitors effectively target all RASG12C mutations and that sotorasib specifically is a potent NRASG12C inhibitor capable of driving clinical responses. These findings have important implications for the treatment of patients with NRASG12C or HRASG12C cancers and could guide design of NRAS or HRAS inhibitors. See related commentary by Seale and Misale, p. 698. This article is featured in Selected Articles from This Issue, p. 695.
Topics: Humans; Membrane Proteins; Proto-Oncogene Proteins p21(ras); GTP Phosphohydrolases; Mutation; Cell Line, Tumor; Colorectal Neoplasms; Antineoplastic Agents; Pyrimidines; Piperazines; Pyridines
PubMed: 38236605
DOI: 10.1158/2159-8290.CD-23-1138 -
The Oncologist Dec 2023Colorectal cancer is the third most common cancer worldwide, and incidence is rising in younger individuals. Anti-EGFR antibodies, including cetuximab and panitumumab,... (Review)
Review
Colorectal cancer is the third most common cancer worldwide, and incidence is rising in younger individuals. Anti-EGFR antibodies, including cetuximab and panitumumab, have been incorporated into standard-of-care practice for patients with advanced disease. Herein, we review the molecular characteristics of these agents and the trials that lead to their approvals. Further, we discuss clinical implications of data regarding biomarkers that dictate treatment selection, different dosing strategies, and side effect management. Finally, we look towards the future and describe contexts in which these agents are currently being investigated clinically with a focus on combinations with MAPK-targeted therapies and immunotherapy. Overall, this review provides historical context, current clinical usage, and future directions for anti-EGFR antibodies in advanced colorectal cancer.
Topics: Humans; Antibodies, Monoclonal; Antineoplastic Agents; Antibodies, Monoclonal, Humanized; ErbB Receptors; Cetuximab; Colorectal Neoplasms
PubMed: 37774394
DOI: 10.1093/oncolo/oyad262 -
Clinical Advances in Hematology &... Nov 2023Colorectal cancer is the third most prevalent cancer type in the United States, with an alarming incidence and mortality rate, especially among individuals younger than... (Review)
Review
Colorectal cancer is the third most prevalent cancer type in the United States, with an alarming incidence and mortality rate, especially among individuals younger than 50 years. The epidermal growth factor receptor (EGFR), essential for cell proliferation and survival, has surfaced as a promising therapeutic target for metastatic colorectal cancer and has demonstrated success in various clinical trials. Monoclonal antibodies such as cetuximab and panitumumab have proven to be effective against EGFR by blocking vital downstream signaling pathways and inhibiting gene transcription and cell proliferation. Despite this promise, most patients eventually develop resistance to anti-EGFR treatment, thereby limiting its long-term efficacy. Genomic alterations, such as mutations in KRAS, NRAS, and BRAF, often bypass the EGFR receptor, promoting resistance to therapy. Although our understanding of primary resistance to anti-EGFR therapy has improved, acquired resistance remains a significant hurdle. This review explores the potential mechanisms underpinning this acquired resistance and strategies to overcome it.
Topics: Humans; Antineoplastic Agents; Antibodies, Monoclonal, Humanized; Colorectal Neoplasms; Drug Resistance, Neoplasm; ErbB Receptors; Colonic Neoplasms
PubMed: 37948593
DOI: No ID Found -
Nature Medicine Mar 2024Certain genetic alterations and right-sided primary tumor location are associated with resistance to anti-epidermal growth factor (EGFR) treatment in metastatic...
Certain genetic alterations and right-sided primary tumor location are associated with resistance to anti-epidermal growth factor (EGFR) treatment in metastatic colorectal cancer (mCRC). The phase 3 PARADIGM trial (n = 802) demonstrated longer overall survival with first-line anti-EGFR (panitumumab) versus antivascular endothelial growth factor (bevacizumab) plus modified FOLFOX6 in patients with RAS wild-type mCRC with left-sided primary tumors. This prespecified exploratory biomarker analysis of PARADIGM (n = 733) evaluated the association between circulating tumor DNA (ctDNA) gene alterations and efficacy outcomes, focusing on a broad panel of gene alterations associated with resistance to EGFR inhibition, including KRAS, NRAS, PTEN and extracellular domain EGFR mutations, HER2 and MET amplifications, and ALK, RET and NTRK1 fusions. Overall survival was prolonged with panitumumab plus modified FOLFOX6 versus bevacizumab plus modified FOLFOX6 in patients with ctDNA that lacked gene alterations in the panel (that is, negative hyperselected; median in the overall population: 40.7 versus 34.4 months; hazard ratio, 0.76; 95% confidence interval, 0.62-0.92) but was similar or inferior with panitumumab in patients with ctDNA that contained any gene alteration in the panel (19.2 versus 22.2 months; hazard ratio, 1.13; 95% confidence interval, 0.83-1.53), regardless of tumor sidedness. Negative hyperselection using ctDNA may guide optimal treatment selection in patients with mCRC. ClinicalTrials.gov registrations: NCT02394834 and NCT02394795 .
Topics: Humans; Panitumumab; Bevacizumab; Antibodies, Monoclonal; Colorectal Neoplasms; Colonic Neoplasms; Rectal Neoplasms; Biomarkers; ErbB Receptors; Antineoplastic Combined Chemotherapy Protocols; Proto-Oncogene Proteins p21(ras)
PubMed: 38347302
DOI: 10.1038/s41591-023-02791-w -
Cancer Discovery Jan 2024To boost KRASG12C inhibitor efficacy and counter cancer cells' ability to mount resistance, combination strategies are being utilized. Findings from the phase III...
To boost KRASG12C inhibitor efficacy and counter cancer cells' ability to mount resistance, combination strategies are being utilized. Findings from the phase III CodeBreaK 300 trial indicate that adding the EGFR inhibitor panitumumab to sotorasib bests standard care for chemorefractory KRASG12C colorectal cancer. Joint SHP2 blockade is another approach that shows signs of activity in reversing acquired KRASG12C inhibitor resistance, according to preliminary phase I data.
Topics: Humans; Antibodies, Monoclonal; Colorectal Neoplasms; ErbB Receptors; Panitumumab; Mutation; Proto-Oncogene Proteins p21(ras)
PubMed: 37921413
DOI: 10.1158/2159-8290.CD-ND2023-0015 -
Pharmaceutics Nov 2023Colorectal cancer (CRC) is one of the deadliest malignancies in the US, ranking fourth after lung, prostate, and breast cancers, respectively, in general populations. It... (Review)
Review
Colorectal cancer (CRC) is one of the deadliest malignancies in the US, ranking fourth after lung, prostate, and breast cancers, respectively, in general populations. It continues to be a menace, and the incidence has been projected to more than double by 2035, especially in underdeveloped countries. This review seeks to provide some insights into the disease progression, currently available treatment options and their challenges, and future perspectives. Searches were conducted in the PubMed search engine in the university's online library. The keywords were "Colorectal Cancer" AND "disease process" OR "disease mechanisms" OR "Current Treatment" OR "Prospects". Selection criteria were original articles published primarily during the period of 2013 through 2023. Abstracts, books and documents, and reviews/systematic reviews were filtered out. Of over 490 thousand articles returned, only about 800 met preliminary selection criteria, 200 were reviewed in detail, but 191 met final selection criteria. Fifty-one other articles were used due to cross-referencing. Although recently considered a disease of lifestyle, CRC incidence appears to be rising in countries with low, low-medium, and medium social demographic indices. CRC can affect all parts of the colon and rectum but is more fatal with poor disease outcomes when it is right-sided. The disease progression usually takes between 7-10 years and can be asymptomatic, making early detection and diagnosis difficult. The CRC tumor microenvironment is made up of different types of cells interacting with each other to promote the growth and proliferation of the tumor cells. Significant advancement has been made in the treatment of colorectal cancer. Notable approaches include surgery, chemotherapy, radiation therapy, and cryotherapy. Chemotherapy, including 5-fluorouracil, irinotecan, oxaliplatin, and leucovorin, plays a significant role in the management of CRC that has been diagnosed at advanced stages. Two classes of monoclonal antibody therapies have been approved by the FDA for the treatment of colorectal cancer: the vascular endothelial growth factor (VEGF) inhibitor, e.g., bevacizumab (Avastin), and the epidermal growth factor receptor (EGFR) inhibitor, e.g., cetuximab (Erbitux) and panitumumab (Verbitix). However, many significant problems are still being experienced with these treatments, mainly off-target effects, toxic side effects, and the associated therapeutic failures of small molecular drugs and the rapid loss of efficacy of mAb therapies. Other novel delivery strategies continue to be investigated, including ligand-based targeting of CRC cells.
PubMed: 38004598
DOI: 10.3390/pharmaceutics15112620