Combining Sotorasib and Panitumumab Extends Survival in Advanced Colorectal Cancer with the KRAS G12C Mutation

Table of Contents

• Key Points
• Background: Why This Research Matters
• How the Study Was Conducted
• Who Participated in the Study
• Key Findings: Progression-Free Survival and Response Rates
• Additional Results: Disease Control and Response Duration
• Safety and Side Effects
• What These Results Mean for Patients
• Limitations of the Study
• Recommendations and Next Steps
• Frequently Asked Questions
• Source Information

Key Points

• In 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.
• 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, 30.2% of the 240-mg group, and 43.1% of the standard-care group.
• The most common side effects of the combination were skin toxicity and low magnesium; few patients discontinued treatment because of side effects.
• Overall survival data were still maturing, so it is not yet known whether the combination extends how long patients live.

Background: Why This Research Matters

Colorectal 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 KRAS G12C. 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.

For 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.

Currently, 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.

Sotorasib 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.

Why 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.

Panitumumab 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.

An 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.

The 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.

How the Study Was Conducted

This 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.

The 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.

Key requirements for participation included:

• Disease progression or recurrence after receiving at least one previous line of therapy for metastatic disease
• A KRAS G12C mutation confirmed by prospective central molecular testing
• Measurable disease according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1
• An 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.
• Adequate organ function

The 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.

Patients were randomly assigned in a 1:1:1 ratio to one of three groups:

1. 960-mg sotorasib–panitumumab group: sotorasib at 960 mg once daily plus panitumumab
2. 240-mg sotorasib–panitumumab group: sotorasib at 240 mg once daily plus panitumumab
3. Standard-care group: the investigator's choice of trifluridine–tipiracil or regorafenib

Randomization 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).

Sotorasib 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.

Trifluridine–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.

Treatment 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.

Some 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.

Tumors 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.

The 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.

The 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.

For 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.

The 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.

Who Participated in the Study

Between 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%).

The 160 patients were assigned as follows:

• 53 patients received sotorasib 960 mg once daily plus panitumumab
• 53 patients received sotorasib 240 mg once daily plus panitumumab
• 54 patients received standard care (37 received trifluridine–tipiracil and 14 received regorafenib)

Three patients in the standard-care group did not receive the assigned treatment. These patients were not included in the safety analysis.

As 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.

The 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.

Key baseline characteristics included:

• Previous antiangiogenic therapy: 84.9% in the 960-mg group, 88.7% in the 240-mg group, and 88.9% in the standard-care group
• Time from initial diagnosis of metastatic disease to randomization of 18 months or more: 54.7% in the 960-mg group, 54.7% in the 240-mg group, and 57.4% in the standard-care group
• ECOG performance-status score of 0: 60.4% in the 960-mg group, 54.7% in the 240-mg group, and 64.8% in the standard-care group
• Colon as the body site at initial diagnosis: 69.8% in the 960-mg group, 60.4% in the 240-mg group, and 68.5% in the standard-care group
• Left-sided tumor location: 52.8% in the 960-mg group, 67.9% in the 240-mg group, and 68.5% in the standard-care group
• Two or more previous lines of anticancer therapy: 86.8% in the 960-mg group, 84.9% in the 240-mg group, and 83.3% in the standard-care group
• Previous treatment with oxaliplatin, irinotecan, and fluoropyrimidine: 92.5% in the 960-mg group, 94.3% in the 240-mg group, and 94.4% in the standard-care group
• Previous treatment with trifluridine and tipiracil: 13.2% in the 960-mg group, 13.2% in the 240-mg group, and 11.1% in the standard-care group
• Previous treatment with regorafenib: 7.5% in the 960-mg group, 1.9% in the 240-mg group, and 3.7% in the standard-care group

Microsatellite 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.

Key Findings: Progression-Free Survival and Response Rates

The 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.

The median progression-free survival results were:

• 960-mg sotorasib–panitumumab group: 5.6 months (95% confidence interval [CI], 4.2 to 6.3)
• 240-mg sotorasib–panitumumab group: 3.9 months (95% CI, 3.6 to 5.7)
• Standard-care group: 2.0 months (95% CI, 1.9 to 3.9)

The 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.

The 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.

Overall 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.

The objective response rate (the percentage of patients whose tumors shrank significantly) was:

• 960-mg sotorasib–panitumumab group: 26.4% (95% CI, 15.3 to 40.3)
• 240-mg sotorasib–panitumumab group: 5.7% (95% CI, 1.2 to 15.7)
• Standard-care group: 0% (95% CI, 0.0 to 6.6)

The 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).

The best overall response in each group was as follows:

• Complete response (no evidence of cancer): 1.9% in the 960-mg group, 0% in the 240-mg group, and 0% in the standard-care group
• Partial response (tumor shrinkage): 24.5% in the 960-mg group, 5.7% in the 240-mg group, and 0% in the standard-care group
• Stable disease (tumor neither grew nor shrank significantly): 45.3% in the 960-mg group, 62.3% in the 240-mg group, and 46.3% in the standard-care group
• Progressive disease (tumor grew): 22.6% in the 960-mg group, 24.5% in the 240-mg group, and 31.5% in the standard-care group

Additional Results: Disease Control and Response Duration

The disease control rate (complete response plus partial response plus stable disease for at least 7 weeks) was:

• 960-mg sotorasib–panitumumab group: 71.7% (95% CI, 57.7 to 83.2)
• 240-mg sotorasib–panitumumab group: 67.9% (95% CI, 53.7 to 80.1)
• Standard-care group: 46.3% (95% CI, 32.6 to 60.4)

For 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).

Safety and Side Effects

Treatment-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.

The most common adverse events observed with sotorasib–panitumumab were skin-related toxic effects and hypomagnesemia (low levels of magnesium in the blood).

The 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:

• 960-mg sotorasib–panitumumab group: 30 patients discontinued sotorasib and 31 discontinued panitumumab
• 240-mg sotorasib–panitumumab group: 34 patients discontinued sotorasib and 35 discontinued panitumumab
• Standard-care group: 46 patients discontinued standard care

The 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.

Other 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.

What These Results Mean for Patients

This 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.

The 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.

The 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.

Importantly, 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.

For 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.

Limitations of the Study

The 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.

The 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.

The 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.

The 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.

Quality-of-life results were collected but not reported in this article.

Recommendations and Next Steps

Based 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.

Patients 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.

Patients 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.

Further 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.

Frequently Asked Questions

What is the KRAS G12C mutation and how common is it in metastatic colorectal cancer?

The 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.

Who was eligible for the CodeBreaK 300 trial of sotorasib plus panitumumab?

Eligible 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.

How much did the combination extend progression-free survival compared with standard care?

In 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.

What were the side effects of sotorasib plus panitumumab, and how many patients stopped treatment because of them?

The 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.

Does the combination improve overall survival?

Overall 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.

What does an objective response rate of 26.4% mean?

The 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.

What should patients with metastatic colorectal cancer do next?

Patients 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.

I have metastatic colorectal cancer with the KRAS G12C mutation and my oncologist recommends trifluridine–tipiracil or regorafenib — when should I seek a second opinion?

A 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.

Source Information

Original article title: Sotorasib plus Panitumumab in Refractory Colorectal Cancer with Mutated KRAS G12C NEJM 2023

Authors: 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

Publication: New England Journal of Medicine, December 7, 2023, Volume 389, Number 23, pages 2125-2139

DOI: 10.1056/NEJMoa2308795

Trial registration: CodeBreaK 300, ClinicalTrials.gov number NCT05198934

Funding: Amgen

This patient-friendly article is based on peer-reviewed research.