{"product_id":"combining-sotorasib-and-panitumumab-extends-survival-in-advanced-colorectal-cancer-with-the-kras-g12c-mutation","title":"Combining Sotorasib and Panitumumab Extends Survival in Advanced Colorectal Cancer with the KRAS G12C Mutation","description":"\u003cp\u003eIn a phase 3 randomized trial, 160 patients had chemorefractory metastatic colorectal cancer carrying the KRAS G12C mutation. Combining sotorasib 960 mg daily with panitumumab extended median progression-free survival to 5.6 months. Standard care gave 2.0 months (hazard ratio 0.48; P=0.005). The objective response rate was 26.4% with the 960-mg combination, 5.7% with the 240-mg combination, and 0% with standard care. Grade 3 or higher treatment-related adverse events occurred in 35.8% of the 960-mg group. These events occurred in 30.2% of the 240-mg group and 43.1% of the standard-care group. Skin toxicity and low magnesium were the most common side effects of the combination.\u003c\/p\u003e\n\n\u003ch1\u003eCombining Sotorasib and Panitumumab Extends Survival in Advanced Colorectal Cancer with the KRAS G12C Mutation\u003c\/h1\u003e\n\n\u003ch2\u003eTable of Contents\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003e\u003ca href=\"#ddn-key-points\"\u003eKey Points\u003c\/a\u003e\u003c\/li\u003e\n\n\u003cli\u003e\u003ca href=\"#background\"\u003eBackground: Why This Research Matters\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#study-methods\"\u003eHow the Study Was Conducted\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#patient-characteristics\"\u003eWho Participated in the Study\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#key-findings\"\u003eKey Findings: Progression-Free Survival and Response Rates\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#secondary-findings\"\u003eAdditional Results: Disease Control and Response Duration\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#safety\"\u003eSafety and Side Effects\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#clinical-implications\"\u003eWhat These Results Mean for Patients\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#limitations\"\u003eLimitations of the Study\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#recommendations\"\u003eRecommendations and Next Steps\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#ddn-faq\"\u003eFrequently Asked Questions\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#source\"\u003eSource Information\u003c\/a\u003e\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003c!-- ddn:keypoints:start --\u003e\n\u003ch2 id=\"ddn-key-points\"\u003eKey Points\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003eIn a phase 3 trial of 160 patients with chemorefractory metastatic colorectal cancer and the KRAS G12C mutation, sotorasib 960 mg plus panitumumab extended median progression-free survival to 5.6 months versus 2.0 months with standard care.\u003c\/li\u003e\n\u003cli\u003eThe objective response rate was 26.4% with the 960-mg combination, 5.7% with the 240-mg combination, and 0% with standard care.\u003c\/li\u003e\n\u003cli\u003eGrade 3 or higher treatment-related adverse events occurred in 35.8% of the 960-mg group, 30.2% of the 240-mg group, and 43.1% of the standard-care group.\u003c\/li\u003e\n\u003cli\u003eThe most common side effects of the combination were skin toxicity and low magnesium; few patients discontinued treatment because of side effects.\u003c\/li\u003e\n\u003cli\u003eOverall survival data were still maturing, so it is not yet known whether the combination extends how long patients live.\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003c!-- ddn:keypoints:end --\u003e\n\n\n\u003ch2 id=\"background\"\u003eBackground: Why This Research Matters\u003c\/h2\u003e\n\n\u003cp\u003eColorectal cancer is one of the most common cancers worldwide. About 3 to 4% of patients with metastatic colorectal cancer (cancer that has spread to other organs) carry a specific genetic change called \u003cstrong\u003eKRAS G12C\u003c\/strong\u003e. This mutation occurs in a gene called the Kirsten rat sarcoma viral oncogene homologue (KRAS). The mutation changes one building block of the protein at position 12, replacing the amino acid glycine with cysteine. This change may be associated with a poor prognosis.\u003c\/p\u003e\n\n\u003cp\u003eFor patients whose cancer has stopped responding to initial treatments, the standard options are limited. These initial treatments usually include fluoropyrimidine-based chemotherapy, with or without bevacizumab. After those treatments stop working, doctors typically turn to two drugs: trifluridine–tipiracil or regorafenib. Both have shown limited effectiveness in this setting. The objective response rate (the percentage of patients whose tumors shrink) is only 1 to 2%. The median progression-free survival (the time before the cancer grows again) is 2.0 months or less. These drugs also cause toxic effects.\u003c\/p\u003e\n\n\u003cp\u003eCurrently, no targeted therapies approved specifically for KRAS-mutated colorectal cancer are selected by a positive biomarker. A biomarker is a measurable indicator, such as a gene mutation, that helps doctors choose the right treatment.\u003c\/p\u003e\n\n\u003cp\u003eSotorasib is a drug that selectively and irreversibly inhibits (blocks) the KRAS G12C protein. By blocking this protein, sotorasib aims to stop signals that drive cancer cell growth and survival. Single-agent KRAS G12C inhibitors, including sotorasib and adagrasib, have improved outcomes in patients with non–small-cell lung cancer that carries the KRAS G12C mutation. However, using a KRAS G12C inhibitor alone has shown limited activity in patients with colorectal cancer.\u003c\/p\u003e\n\n\u003cp\u003eWhy does the drug work less well in colorectal cancer? Research shows that cancer cells develop resistance to KRAS G12C inhibition. This resistance happens mainly through reactivation of the epidermal growth factor receptor (EGFR) pathway, a signaling system that promotes cell growth. Preclinical studies (laboratory research done before human trials) showed that blocking both KRAS G12C and EGFR at the same time has synergistic activity. Synergistic means the combined effect is greater than the sum of the individual effects.\u003c\/p\u003e\n\n\u003cp\u003ePanitumumab is an EGFR inhibitor. In colorectal cancer with the KRAS G12C mutation, EGFR inhibitors such as cetuximab and panitumumab do not work when used alone. The strategy of blocking both KRAS G12C and EGFR was designed to overcome treatment resistance in this patient population.\u003c\/p\u003e\n\n\u003cp\u003eAn earlier single-group phase 1b trial called CodeBreaK 101 tested this combination. In that trial, the confirmed response rate was 30% with sotorasib plus panitumumab, compared with 9.7% with sotorasib alone. These promising results led to the larger phase 3 trial described here.\u003c\/p\u003e\n\n\u003cp\u003eThe researchers also wanted to compare two different doses of sotorasib. The recommended phase 2 dose of sotorasib is 960 mg once daily. A lower dose of 240 mg once daily was also tested because sotorasib has nonlinear pharmacokinetic properties. Pharmacokinetics refers to how the body absorbs, distributes, and clears a drug. In recent years, researchers have placed greater emphasis on understanding the relationship between drug dose and both effectiveness and safety. This helps doctors select the best dose that maximizes benefit while minimizing toxic effects.\u003c\/p\u003e\n\n\u003ch2 id=\"study-methods\"\u003eHow the Study Was Conducted\u003c\/h2\u003e\n\n\u003cp\u003eThis was a phase 3, multicenter, open-label, randomized, active-controlled trial. \"Phase 3\" means it is a large study designed to confirm effectiveness. \"Multicenter\" means it took place at many hospitals. \"Open-label\" means both patients and doctors knew which treatment was given. \"Randomized\" means patients were assigned to treatment groups by chance. \"Active-controlled\" means the comparison group received an active treatment rather than a placebo.\u003c\/p\u003e\n\n\u003cp\u003eThe trial is called CodeBreaK 300. It enrolled adult patients with metastatic colorectal cancer carrying the KRAS G12C mutation. Patients must not have received previous treatment with a KRAS G12C inhibitor.\u003c\/p\u003e\n\n\u003cp\u003eKey requirements for participation included:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003eDisease progression or recurrence after receiving at least one previous line of therapy for metastatic disease\u003c\/li\u003e\n\u003cli\u003eA KRAS G12C mutation confirmed by prospective central molecular testing\u003c\/li\u003e\n\u003cli\u003eMeasurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1\u003c\/li\u003e\n\u003cli\u003eAn Eastern Cooperative Oncology Group (ECOG) performance-status score of 0, 1, or 2. This score measures how well a patient can carry out daily activities. It ranges from 0 to 5, with higher scores indicating greater disability.\u003c\/li\u003e\n\u003cli\u003eAdequate organ function\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThe previous line of therapy for metastatic disease had to include fluoropyrimidine, oxaliplatin, and irinotecan. An exception was made if the patient had unacceptable side effects from these drugs. In that case, the patient could receive trifluridine–tipiracil or regorafenib as the next line of therapy if the investigator deemed it appropriate and the medical monitor approved.\u003c\/p\u003e\n\n\u003cp\u003ePatients were randomly assigned in a 1:1:1 ratio to one of three groups:\u003c\/p\u003e\n\n\u003col\u003e\n\u003cli\u003e\n\u003cstrong\u003e960-mg sotorasib–panitumumab group:\u003c\/strong\u003e sotorasib at 960 mg once daily plus panitumumab\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003e240-mg sotorasib–panitumumab group:\u003c\/strong\u003e sotorasib at 240 mg once daily plus panitumumab\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eStandard-care group:\u003c\/strong\u003e the investigator's choice of trifluridine–tipiracil or regorafenib\u003c\/li\u003e\n\u003c\/ol\u003e\n\n\u003cp\u003eRandomization was stratified (balanced) according to three factors. The first factor was previous use of antiangiogenic therapy (yes or no). The second factor was the time from initial diagnosis of metastatic disease to randomization (18 months or more versus less than 18 months). The third factor was ECOG performance-status score (0 or 1 versus 2).\u003c\/p\u003e\n\n\u003cp\u003eSotorasib was given orally once daily. Panitumumab was given as an intravenous infusion at a dose of 6 mg per kilogram of body weight every 2 weeks. Each treatment cycle lasted 28 days.\u003c\/p\u003e\n\n\u003cp\u003eTrifluridine–tipiracil was given orally twice daily at a starting dose of 35 mg per square meter of body-surface area. The maximum dose was 80 mg per dose, or 75 mg per dose for patients in Japan, based on the trifluridine component. Patients took this drug on days 1 through 5 and days 8 through 12 of each 28-day cycle. Regorafenib was given orally at a dose of 160 mg once daily for the first 21 days of each 28-day cycle.\u003c\/p\u003e\n\n\u003cp\u003eTreatment continued until one of the following occurred first. These events were disease progression as assessed by blinded independent central review, unacceptable toxic effects, initiation of another anticancer therapy, withdrawal of consent, or death. \"Blinded independent central review\" means that a group of radiologists who did not know which treatment each patient received reviewed the imaging scans. This reduces bias in assessing whether the cancer has grown.\u003c\/p\u003e\n\n\u003cp\u003eSome patients stopped treatment before disease progression occurred, for example because of unacceptable toxic effects. Those patients were followed until disease progression was seen on imaging, consent was withdrawn, or another anticancer therapy was started. Patients were to be followed for up to 2 years after the last patient enrolled, or until consent was withdrawn, the patient was lost to follow-up, or death occurred.\u003c\/p\u003e\n\n\u003cp\u003eTumors were assessed using computed tomography (CT), magnetic resonance imaging (MRI), or both, according to RECIST version 1.1. These assessments happened at baseline and every 8 weeks (plus or minus 7 days). Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Blood samples were collected to measure plasma and serum concentrations of sotorasib and panitumumab.\u003c\/p\u003e\n\n\u003cp\u003eThe primary end point was progression-free survival. This was defined as the time from randomization to disease progression (as assessed by blinded independent central review according to RECIST version 1.1) or death from any cause, whichever occurred first. Secondary end points included overall survival, objective response, duration of response, time to response, disease control, safety, quality of life, and pharmacokinetics.\u003c\/p\u003e\n\n\u003cp\u003eThe trial was designed by the sponsor, Amgen. An independent data and safety monitoring committee oversaw the trial and assessed safety at prespecified interim analyses. The trial followed Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. The protocol was approved by the institutional review board or independent ethics committee at each participating site. All patients provided written informed consent.\u003c\/p\u003e\n\n\u003cp\u003eFor the statistical analysis, approximately 153 patients were planned for enrollment. Researchers anticipated that approximately 90 events would occur. This would give the trial 90% power to detect superiority of each sotorasib–panitumumab group over standard care. The assumed hazard ratio for disease progression or death was 0.4. A hazard ratio compares the risk of an event between two groups. A hazard ratio of 0.4 would mean a 60% reduction in risk.\u003c\/p\u003e\n\n\u003cp\u003eThe overall type I error was preserved at a two-sided alpha level of 5% using the graphical method of Maurer–Bretz. Hierarchical testing was performed for progression-free survival first, followed by overall survival, then objective response. Progression-free survival in the 960-mg group compared with standard care was tested first at one half of the alpha (two-sided alpha level of 2.5%). If statistical significance was shown, one fourth of that alpha portion would be propagated to test progression-free survival in the 240-mg group compared with standard care. The other half of the alpha (3.125%) would also be used.\u003c\/p\u003e\n\n\u003ch2 id=\"patient-characteristics\"\u003eWho Participated in the Study\u003c\/h2\u003e\n\n\u003cp\u003eBetween April 19, 2022, and March 14, 2023, a total of 219 patients were screened at 76 sites across 12 countries. Of these, 160 patients were eligible and underwent randomization. The patients came from Europe (65.6%), Asia (22.5%), North America (10.6%), and other regions (1.2%).\u003c\/p\u003e\n\n\u003cp\u003eThe 160 patients were assigned as follows:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e53 patients received sotorasib 960 mg once daily plus panitumumab\u003c\/li\u003e\n\u003cli\u003e53 patients received sotorasib 240 mg once daily plus panitumumab\u003c\/li\u003e\n\u003cli\u003e54 patients received standard care (37 received trifluridine–tipiracil and 14 received regorafenib)\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThree patients in the standard-care group did not receive the assigned treatment. These patients were not included in the safety analysis.\u003c\/p\u003e\n\n\u003cp\u003eAs of June 15, 2023, disease progression or death had occurred in 91 patients. This triggered the data-cutoff date of the primary analysis on June 19, 2023.\u003c\/p\u003e\n\n\u003cp\u003eThe demographic and clinical characteristics of patients at baseline were generally balanced across the three groups. The median age was 62.0 years, with a range of 34 to 82 years. Overall, 49.4% of patients were men.\u003c\/p\u003e\n\n\u003cp\u003eKey baseline characteristics included:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003ePrevious antiangiogenic therapy:\u003c\/strong\u003e 84.9% in the 960-mg group, 88.7% in the 240-mg group, and 88.9% in the standard-care group\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eTime from initial diagnosis of metastatic disease to randomization of 18 months or more:\u003c\/strong\u003e 54.7% in the 960-mg group, 54.7% in the 240-mg group, and 57.4% in the standard-care group\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eECOG performance-status score of 0:\u003c\/strong\u003e 60.4% in the 960-mg group, 54.7% in the 240-mg group, and 64.8% in the standard-care group\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eColon as the body site at initial diagnosis:\u003c\/strong\u003e 69.8% in the 960-mg group, 60.4% in the 240-mg group, and 68.5% in the standard-care group\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eLeft-sided tumor location:\u003c\/strong\u003e 52.8% in the 960-mg group, 67.9% in the 240-mg group, and 68.5% in the standard-care group\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eTwo or more previous lines of anticancer therapy:\u003c\/strong\u003e 86.8% in the 960-mg group, 84.9% in the 240-mg group, and 83.3% in the standard-care group\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003ePrevious treatment with oxaliplatin, irinotecan, and fluoropyrimidine:\u003c\/strong\u003e 92.5% in the 960-mg group, 94.3% in the 240-mg group, and 94.4% in the standard-care group\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003ePrevious treatment with trifluridine and tipiracil:\u003c\/strong\u003e 13.2% in the 960-mg group, 13.2% in the 240-mg group, and 11.1% in the standard-care group\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003ePrevious treatment with regorafenib:\u003c\/strong\u003e 7.5% in the 960-mg group, 1.9% in the 240-mg group, and 3.7% in the standard-care group\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eMicrosatellite instability status was also recorded. Microsatellite instability is a genetic feature that can affect cancer behavior and treatment response. Most patients had stable microsatellite status: 79.2% in the 960-mg group, 79.2% in the 240-mg group, and 79.6% in the standard-care group. High microsatellite instability was found in 1.9% of the 960-mg group, 0% of the 240-mg group, and 0% of the standard-care group. Low microsatellite instability was found in 5.7% of the 960-mg group, 3.8% of the 240-mg group, and 5.6% of the standard-care group. Status was unknown or not tested in 13.2% of the 960-mg group, 17.0% of the 240-mg group, and 14.8% of the standard-care group.\u003c\/p\u003e\n\n\u003ch2 id=\"key-findings\"\u003eKey Findings: Progression-Free Survival and Response Rates\u003c\/h2\u003e\n\n\u003cp\u003eThe study met its primary end point. After a median follow-up of 7.8 months (range, 0.1 to 13.9), the median progression-free survival was significantly longer in the 960-mg sotorasib–panitumumab group than in the standard-care group.\u003c\/p\u003e\n\n\u003cp\u003eThe median progression-free survival results were:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003e960-mg sotorasib–panitumumab group:\u003c\/strong\u003e 5.6 months (95% confidence interval [CI], 4.2 to 6.3)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003e240-mg sotorasib–panitumumab group:\u003c\/strong\u003e 3.9 months (95% CI, 3.6 to 5.7)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eStandard-care group:\u003c\/strong\u003e 2.0 months (95% CI, 1.9 to 3.9)\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThe hazard ratio for disease progression or death in the 960-mg sotorasib–panitumumab group compared with the standard-care group was 0.48 (95% CI, 0.30 to 0.78; P=0.005). The P value of 0.005 indicates that there is less than a 0.5% probability that this result occurred by chance alone.\u003c\/p\u003e\n\n\u003cp\u003eThe hazard ratio in the 240-mg sotorasib–panitumumab group compared with the standard-care group was 0.59 (95% CI, 0.37 to 0.95; P=0.036). The P value of 0.036 indicates that there is less than a 3.6% probability that this result occurred by chance.\u003c\/p\u003e\n\n\u003cp\u003eOverall survival data are still maturing. This means that not enough patients had died at the time of this analysis to draw firm conclusions about whether the combination extends life.\u003c\/p\u003e\n\n\u003cp\u003eThe objective response rate (the percentage of patients whose tumors shrank significantly) was:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003e960-mg sotorasib–panitumumab group:\u003c\/strong\u003e 26.4% (95% CI, 15.3 to 40.3)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003e240-mg sotorasib–panitumumab group:\u003c\/strong\u003e 5.7% (95% CI, 1.2 to 15.7)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eStandard-care group:\u003c\/strong\u003e 0% (95% CI, 0.0 to 6.6)\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThe difference in proportions between the 960-mg group and the standard-care group was 27.0 percentage points (95% CI, 14.9 to 39.0). The difference between the 240-mg group and the standard-care group was 5.5 percentage points (95% CI, –0.7 to 11.8).\u003c\/p\u003e\n\n\u003cp\u003eThe best overall response in each group was as follows:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003eComplete response (no evidence of cancer):\u003c\/strong\u003e 1.9% in the 960-mg group, 0% in the 240-mg group, and 0% in the standard-care group\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003ePartial response (tumor shrinkage):\u003c\/strong\u003e 24.5% in the 960-mg group, 5.7% in the 240-mg group, and 0% in the standard-care group\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eStable disease (tumor neither grew nor shrank significantly):\u003c\/strong\u003e 45.3% in the 960-mg group, 62.3% in the 240-mg group, and 46.3% in the standard-care group\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eProgressive disease (tumor grew):\u003c\/strong\u003e 22.6% in the 960-mg group, 24.5% in the 240-mg group, and 31.5% in the standard-care group\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003ch2 id=\"secondary-findings\"\u003eAdditional Results: Disease Control and Response Duration\u003c\/h2\u003e\n\n\u003cp\u003eThe disease control rate (complete response plus partial response plus stable disease for at least 7 weeks) was:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003e960-mg sotorasib–panitumumab group:\u003c\/strong\u003e 71.7% (95% CI, 57.7 to 83.2)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003e240-mg sotorasib–panitumumab group:\u003c\/strong\u003e 67.9% (95% CI, 53.7 to 80.1)\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eStandard-care group:\u003c\/strong\u003e 46.3% (95% CI, 32.6 to 60.4)\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eFor patients who responded to treatment, the median duration of response in the 960-mg sotorasib–panitumumab group was 4.4 months (95% CI, 3.6 to not reached). The median time to response in the 960-mg group was 2.1 months (range, 1.9 to 3.9). In the 240-mg group, the median time to response was 1.8 months (range, 1.7 to 1.9).\u003c\/p\u003e\n\n\u003ch2 id=\"safety\"\u003eSafety and Side Effects\u003c\/h2\u003e\n\n\u003cp\u003eTreatment-related adverse events of grade 3 or higher occurred in 35.8% of patients in the 960-mg sotorasib–panitumumab group, 30.2% in the 240-mg sotorasib–panitumumab group, and 43.1% in the standard-care group. Grade 3 adverse events are serious but not life-threatening. They often require medical treatment or a pause in treatment.\u003c\/p\u003e\n\n\u003cp\u003eThe most common adverse events observed with sotorasib–panitumumab were skin-related toxic effects and hypomagnesemia (low levels of magnesium in the blood).\u003c\/p\u003e\n\n\u003cp\u003eThe researchers noted that the toxic effects were as expected for either agent alone. Importantly, few patients discontinued treatment because of side effects. The rates of treatment discontinuation were:\u003c\/p\u003e\n\n\u003cul\u003e\n\u003cli\u003e\n\u003cstrong\u003e960-mg sotorasib–panitumumab group:\u003c\/strong\u003e 30 patients discontinued sotorasib and 31 discontinued panitumumab\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003e240-mg sotorasib–panitumumab group:\u003c\/strong\u003e 34 patients discontinued sotorasib and 35 discontinued panitumumab\u003c\/li\u003e\n\u003cli\u003e\n\u003cstrong\u003eStandard-care group:\u003c\/strong\u003e 46 patients discontinued standard care\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThe most common reason for discontinuation was disease progression. In the 960-mg group, 24 patients discontinued sotorasib because of disease progression. In the 240-mg group, 32 patients discontinued sotorasib because of disease progression. In the standard-care group, 40 patients discontinued because of disease progression.\u003c\/p\u003e\n\n\u003cp\u003eOther reasons for discontinuation included death, adverse events, nonadherence, and withdrawal of consent. In the 960-mg group, 2 patients died, 2 were nonadherent, and 2 withdrew consent. In the 240-mg group, 1 patient died and 1 had an adverse event. In the standard-care group, 4 patients died and 2 had adverse events.\u003c\/p\u003e\n\n\u003ch2 id=\"clinical-implications\"\u003eWhat These Results Mean for Patients\u003c\/h2\u003e\n\n\u003cp\u003eThis phase 3 trial showed that combining sotorasib 960 mg with panitumumab significantly extended the time before cancer progressed compared with standard late-line treatments. The median progression-free survival nearly tripled, from 2.0 months with standard care to 5.6 months with the 960-mg combination.\u003c\/p\u003e\n\n\u003cp\u003eThe objective response rate was also substantially higher with the 960-mg combination. More than one in four patients (26.4%) in the 960-mg group had their tumors shrink significantly, compared with none (0%) in the standard-care group. This is a meaningful difference for patients who have already received multiple lines of therapy.\u003c\/p\u003e\n\n\u003cp\u003eThe 960-mg dose performed better than the 240-mg dose on both progression-free survival and objective response. This finding supports using the higher dose in this patient population.\u003c\/p\u003e\n\n\u003cp\u003eImportantly, the combination did not produce more severe side effects than standard care. In fact, grade 3 or higher treatment-related adverse events were less common in the 960-mg combination group (35.8%) than in the standard-care group (43.1%). The side effects that did occur, mainly skin toxicity and low magnesium, were consistent with what doctors already expect from these drugs when used individually.\u003c\/p\u003e\n\n\u003cp\u003eFor patients with chemorefractory metastatic colorectal cancer carrying the KRAS G12C mutation, this combination represents a potential new treatment option. The KRAS G12C mutation occurs in approximately 3 to 4% of patients with metastatic colorectal cancer. Patients with this mutation may benefit from molecular testing to identify whether they are candidates for this targeted combination.\u003c\/p\u003e\n\n\u003ch2 id=\"limitations\"\u003eLimitations of the Study\u003c\/h2\u003e\n\n\u003cp\u003eThe overall survival data were still maturing at the time of this analysis. This means the study could not yet determine whether the combination extends how long patients live. The trial is planned to perform a final overall survival analysis after approximately 80 deaths have been reported, which is after 50% of the patients have died. The researchers noted that the expected number of deaths at the time of the final analysis does not provide sufficient power to detect the hypothesized difference in survival.\u003c\/p\u003e\n\n\u003cp\u003eThe median follow-up was 7.8 months, with a range of 0.1 to 13.9 months. This is a relatively short follow-up period. Longer follow-up will be needed to fully understand the duration of benefit and long-term safety.\u003c\/p\u003e\n\n\u003cp\u003eThe trial was open-label, meaning patients and doctors knew which treatment was given. This could potentially influence how side effects are reported, although the primary end point of progression-free survival was assessed by blinded independent central review to reduce bias.\u003c\/p\u003e\n\n\u003cp\u003eThe study enrolled 160 patients, which is a relatively small number. This reflects the rarity of the KRAS G12C mutation in colorectal cancer, which occurs in only 3 to 4% of patients.\u003c\/p\u003e\n\n\u003cp\u003eQuality-of-life results were collected but not reported in this article.\u003c\/p\u003e\n\n\u003ch2 id=\"recommendations\"\u003eRecommendations and Next Steps\u003c\/h2\u003e\n\n\u003cp\u003eBased on these results, the combination of sotorasib 960 mg once daily plus panitumumab may be considered a new treatment option. This option is for patients with chemorefractory metastatic colorectal cancer carrying the KRAS G12C mutation. The 960-mg dose of sotorasib is recommended over the 240-mg dose based on the superior progression-free survival and response rates observed.\u003c\/p\u003e\n\n\u003cp\u003ePatients with metastatic colorectal cancer should discuss molecular testing with their healthcare team. Identifying a KRAS G12C mutation is essential for determining whether this combination is appropriate. The mutation is found in approximately 3 to 4% of patients with metastatic colorectal cancer.\u003c\/p\u003e\n\n\u003cp\u003ePatients receiving this combination should be monitored for skin-related toxic effects and low magnesium levels. These were the most common side effects. However, the overall rate of severe side effects was lower with the combination than with standard care, and few patients discontinued treatment because of side effects.\u003c\/p\u003e\n\n\u003cp\u003eFurther research will continue to follow patients in this trial to determine the effect on overall survival. Additional studies may explore this combination in earlier lines of therapy or in combination with other treatments.\u003c\/p\u003e\n\n\u003c!-- ddn:faq:start --\u003e\n\u003ch2 id=\"ddn-faq\"\u003eFrequently Asked Questions\u003c\/h2\u003e\n\u003ch3\u003eWhat is the KRAS G12C mutation and how common is it in metastatic colorectal cancer?\u003c\/h3\u003e\n\u003cp\u003eThe KRAS G12C mutation is a specific genetic change in a gene called KRAS. It changes one building block of the protein at position 12, replacing glycine with cysteine. This mutation occurs in about 3 to 4% of patients with metastatic colorectal cancer, and it may be associated with a poor prognosis.\u003c\/p\u003e\n\u003ch3\u003eWho was eligible for the CodeBreaK 300 trial of sotorasib plus panitumumab?\u003c\/h3\u003e\n\u003cp\u003eEligible patients were adults with metastatic colorectal cancer carrying the KRAS G12C mutation. They had disease progression after at least one prior therapy for metastatic disease, had not received a KRAS G12C inhibitor, had measurable disease, and had an ECOG performance status of 0, 1, or 2. Prior therapy had to include fluoropyrimidine, oxaliplatin, and irinotecan.\u003c\/p\u003e\n\u003ch3\u003eHow much did the combination extend progression-free survival compared with standard care?\u003c\/h3\u003e\n\u003cp\u003eIn the trial, median progression-free survival was 5.6 months with sotorasib 960 mg plus panitumumab, compared with 2.0 months with standard care. This means the time before the cancer grew again was nearly tripled. The hazard ratio was 0.48 (95% CI, 0.30 to 0.78), indicating a lower risk of disease progression or death with the 960-mg combination compared with standard care.\u003c\/p\u003e\n\u003ch3\u003eWhat were the side effects of sotorasib plus panitumumab, and how many patients stopped treatment because of them?\u003c\/h3\u003e\n\u003cp\u003eThe most common side effects were skin-related toxic effects and low magnesium levels. Grade 3 or higher treatment-related adverse events occurred in 35.8% of patients on the 960-mg combination, compared with 43.1% on standard care. Few patients discontinued treatment because of side effects; the most common reason for discontinuation was disease progression.\u003c\/p\u003e\n\u003ch3\u003eDoes the combination improve overall survival?\u003c\/h3\u003e\n\u003cp\u003eOverall survival data were still maturing at the time of this analysis, meaning not enough patients had died to draw firm conclusions about whether the combination extends life. The trial is planned to perform a final overall survival analysis after approximately 80 deaths have been reported, but the researchers noted this may not provide sufficient power to detect a survival difference.\u003c\/p\u003e\n\u003ch3\u003eWhat does an objective response rate of 26.4% mean?\u003c\/h3\u003e\n\u003cp\u003eThe objective response rate is the percentage of patients whose tumors shrank significantly. In the trial, 26.4% of patients receiving sotorasib 960 mg plus panitumumab had a response, compared with 0% receiving standard care. This means more than one in four patients in the 960-mg group had their tumors shrink.\u003c\/p\u003e\n\u003ch3\u003eWhat should patients with metastatic colorectal cancer do next?\u003c\/h3\u003e\n\u003cp\u003ePatients with metastatic colorectal cancer should discuss molecular testing with their healthcare team. Identifying a KRAS G12C mutation is essential for determining whether this combination is appropriate. The mutation is found in about 3 to 4% of patients with metastatic colorectal cancer. Those receiving the combination should be monitored for skin toxicity and low magnesium levels.\u003c\/p\u003e\n\u003ch3\u003eI have metastatic colorectal cancer with the KRAS G12C mutation and my oncologist recommends trifluridine–tipiracil or regorafenib — when should I seek a second opinion?\u003c\/h3\u003e\n\u003cp\u003eA second opinion is worth seeking when standard late-line options are being considered for chemorefractory metastatic colorectal cancer with the KRAS G12C mutation. In a phase 3 trial, sotorasib 960 mg daily plus panitumumab extended median progression-free survival to 5.6 months versus 2.0 months with standard care, and 26.4% of patients had tumors shrink significantly versus 0%. The mutation occurs in about 3 to 4% of patients with metastatic colorectal cancer, so molecular testing matters. Diagnostic Detectives Network provides independent expert second opinions.\u003c\/p\u003e\n\u003c!-- ddn:faq:end --\u003e\n\n\u003ch2 id=\"source\"\u003eSource Information\u003c\/h2\u003e\n\n\u003cp\u003e\u003cstrong\u003eOriginal article title:\u003c\/strong\u003e Sotorasib plus Panitumumab in Refractory Colorectal Cancer with Mutated KRAS G12C NEJM 2023\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eAuthors:\u003c\/strong\u003e M.G. Fakih, L. Salvatore, T. Esaki, D.P. Modest, D.P. Lopez-Bravo, J. Taieb, M.V. Karamouzis, E. Ruiz-Garcia, T.-W. Kim, Y. Kuboki, F. Meriggi, D. Cunningham, K.-H. Yeh, E. Chan, J. Chao, Y. Saportas, Q. Tran, C. Cremolini, and F. Pietrantonio\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003ePublication:\u003c\/strong\u003e New England Journal of Medicine, December 7, 2023, Volume 389, Number 23, pages 2125-2139\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eDOI:\u003c\/strong\u003e 10.1056\/NEJMoa2308795\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eTrial registration:\u003c\/strong\u003e CodeBreaK 300, ClinicalTrials.gov number NCT05198934\u003c\/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c\/strong\u003e Amgen\u003c\/p\u003e\n\n\u003cp\u003e\u003cem\u003eThis patient-friendly article is based on peer-reviewed research.\u003c\/em\u003e\u003c\/p\u003e","brand":"DiagnosticDetectives.Com","offers":[{"title":"Default Title","offer_id":47919021326492,"sku":null,"price":0.0,"currency_code":"USD","in_stock":true}],"url":"https:\/\/diagnosticdetectives.com\/products\/combining-sotorasib-and-panitumumab-extends-survival-in-advanced-colorectal-cancer-with-the-kras-g12c-mutation","provider":"DiagnosticDetectives.Com","version":"1.0","type":"link"}