Sotorasib Combo vs Pembrolizumab Combo for Advanced Lung Cancer

Recruiting at 502 trial locations

Overseen By Amgen Call Center

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Amgen

Disqualifiers: Mixed histology NSCLC, Brain metastases, GI tract disease, Myocardial infarction, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: Approximately 5.5 years

750 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two different treatment combinations for advanced lung cancer. One group receives sotorasib (a targeted therapy) with chemotherapy, while the other takes pembrolizumab (an immunotherapy) with chemotherapy. The goal is to determine which combination helps patients live longer without cancer progression. This trial targets individuals with a specific type of advanced lung cancer (non-squamous NSCLC with a KRAS mutation) who have not received other treatments for their metastatic cancer. As a Phase 3 trial, it represents the final step before FDA approval, providing patients an opportunity to access potentially effective treatments early.

Do I need to stop my current medications for the trial?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that both sotorasib and pembrolizumab have been studied for their safety.

Sotorasib is generally well-tolerated by patients with advanced lung cancer, particularly those with a KRAS G12C mutation. Common side effects include diarrhea, reported in 155 out of 456 cases. Adjusting the dose can manage these risks. The FDA has approved sotorasib for a specific type of lung cancer, indicating a certain level of safety.

Pembrolizumab is a well-known treatment for various cancers, with a well-documented safety record. Patients might experience side effects like tiredness, cough, and joint pain, but these are usually mild and manageable. It is also FDA-approved for treating lung cancer, which supports its safety.

Both treatments are being tested with chemotherapy drugs carboplatin and pemetrexed, which also have known safety records. Researchers will closely monitor participants in clinical trials to manage any side effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments because they offer new ways to tackle advanced lung cancer. Sotorasib is unique because it targets a specific mutation in the KRAS gene, which has been notoriously difficult to treat. This is a significant departure from standard treatments like pembrolizumab, which generally focus on boosting the immune system to fight cancer cells. On the other hand, pembrolizumab, already a well-known immunotherapy, is being tested in combination with other drugs to potentially enhance its effectiveness. These innovative approaches could lead to more personalized and effective treatment options for patients facing this challenging condition.

What evidence suggests that this trial's treatments could be effective for advanced lung cancer?

This trial will compare two treatment combinations for advanced lung cancer. One arm will study Sotorasib combined with carboplatin and pemetrexed. Research has shown that Sotorasib is promising for treating advanced lung cancer, especially in patients with a specific KRAS mutation. In one study, 41% of patients responded well to Sotorasib, living longer without their cancer worsening for about 6.3 months. Patients lived for about 12.5 months after starting treatment, a significant improvement compared to treatments like docetaxel.

The other arm will study Pembrolizumab combined with carboplatin and pemetrexed. When used with chemotherapy, Pembrolizumab has effectively helped many lung cancer patients live longer. This common treatment aids the immune system in finding and destroying cancer cells. Using it with chemotherapy has been a standard method for advanced lung cancer, showing significant benefits in extending patient survival. ^{4 6 7 8 9}

Who Is on the Research Team?

MD

Principal Investigator

Amgen

Are You a Good Fit for This Trial?

This trial is for adults with advanced non-squamous Non-Small Cell Lung Cancer (NSCLC) that has a specific mutation (KRAS p. G12C) and no PD-L1 expression. They should not have had cancer treatment in the metastatic setting, be relatively fit (ECOG ≤ 1), and able to take oral medication.

Inclusion Criteria

I haven't had any systemic anticancer therapy for incurable cancer.

My advanced lung cancer is KRAS G12C mutation positive and PD-L1 negative.

I am fully active and can carry on all pre-disease activities without restriction.

Exclusion Criteria

I have brain metastases that cause symptoms.

My lung cancer is mixed type with specific cell features.

I have been treated with a KRAS G12C inhibitor before.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either sotorasib with platinum doublet chemotherapy or pembrolizumab with platinum doublet chemotherapy

Approximately 5.5 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Pembrolizumab
• Sotorasib

Trial Overview The study compares two treatments: Sotorasib with platinum chemotherapy versus Pembrolizumab with the same chemo, focusing on how long patients live without their cancer getting worse.

How Is the Trial Designed?

Group I: Sotorasib combined with carboplatin and pemetrexed Experimental Treatment 1 Intervention

Sotorasib administered in combination with carboplatin and pemetrexed.

Group II: Pembrolizumab combined with carboplatin and pemetrexed Active Control 1 Intervention

Pembrolizumab administered in combination with carboplatin and pemetrexed.

Pembrolizumab is already approved in United States, European Union, United Kingdom for the following indications:

Approved in United States as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in European Union as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in United Kingdom as KEYTRUDA for:

• Untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1

Who Is Running the Clinical Trial?

Amgen

Lead Sponsor

Trials

1,508

Recruited

1,433,000+

Founded

1980

Headquarters

Thousand Oaks, USA

Known For

Human Therapeutics

Top Products

Enbrel, Prolia, Neulasta, Otezla

Robert A. Bradway

Amgen

Chief Executive Officer since 2012

MBA from Harvard Business School

Paul Burton

Amgen

Chief Medical Officer since 2023

MD from University of London, PhD in Molecular and Cellular Biology from Imperial College London

Published Research Related to This Trial

In a study of 123 patients with advanced nonsquamous NSCLC, the combination of pembrolizumab and pemetrexed-carboplatin (PC) significantly improved the objective response rate (56.7% vs. 30.2% with PC alone) and progression-free survival (PFS) compared to PC alone, with a hazard ratio (HR) of 0.53.

The updated analysis showed a favorable overall survival (OS) hazard ratio of 0.56 for the pembrolizumab plus PC group, indicating a significant survival benefit, although 41% of patients experienced grade 3 to 5 treatment-related adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

24-Month Overall Survival from KEYNOTE-021 Cohort G: Pemetrexed and Carboplatin with or without Pembrolizumab as First-Line Therapy for Advanced Nonsquamous Non-Small Cell Lung Cancer. Borghaei, H., Langer, CJ., Gadgeel, S., et al.[2022]

In a 2-year follow-up study of 20 patients with advanced non-small cell lung cancer (NSCLC), the combination of autologous NK cell treatment (SNK01) with pembrolizumab significantly improved overall survival (OS) rates to 58.3% compared to 16.7% for pembrolizumab monotherapy.

The study also found that progression-free survival (PFS) was significantly higher in the group receiving the combination treatment, indicating that NK cells can enhance the effectiveness of pembrolizumab in treating NSCLC, although further research with a larger sample size is needed to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Two-year efficacy of SNK01 plus pembrolizumab for non-small cell lung cancer: Expanded observations from a phase I/IIa randomized controlled trial. Park, HJ., Kim, YM., Jung, JS., et al.[2022]

In the KEYNOTE-024 study involving 305 patients with untreated advanced non-small-cell lung cancer, pembrolizumab significantly improved overall survival (OS) compared to platinum-based chemotherapy, with a median OS of 30.0 months versus 14.2 months for chemotherapy.

Pembrolizumab also had a better safety profile, with fewer treatment-related severe adverse events (31.2% for pembrolizumab vs. 53.3% for chemotherapy), indicating it is a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-Based Chemotherapy for Advanced Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score of 50% or Greater. Reck, M., Rodríguez-Abreu, D., Robinson, AG., et al.[2022]

Pembrolizumab monotherapy significantly improved quality-adjusted survival (Q-TWiST) by 2.49 months compared to platinum-based chemotherapy and by 2.29 months compared to docetaxel in patients with advanced non-small cell lung cancer, indicating its efficacy in enhancing patient quality of life.

The benefits of pembrolizumab continued to increase over time, suggesting that it not only offers longer overall survival but also fewer treatment-related adverse events compared to traditional chemotherapy options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Q-TWiST Analysis to Assess Benefit-Risk of Pembrolizumab in Patients with PD-L1-Positive Advanced or Metastatic Non-small Cell Lung Cancer. Huang, M., Pietanza, MC., Samkari, A., et al.[2020]

In a real-life study of 121 patients with advanced non-squamous non-small cell lung cancer, the combination of pembrolizumab and chemotherapy resulted in a median progression-free survival of 9 months and overall survival of 20.6 months, demonstrating its efficacy as a first-line treatment.

The treatment was generally well-tolerated, with manageable side effects; however, 17.5% of patients experienced grade 3-4 adverse events, and there were two treatment-related deaths, indicating the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab plus pemetrexed-carboplatin combination in first-line treatment of advanced non-squamous non-small cell lung cancer: a multicenter real-life study (CAP29). Renaud, E., Ricordel, C., Corre, R., et al.[2023]

This trial aims to compare the effectiveness of pembrolizumab combined with chemotherapy versus pembrolizumab alone in patients with advanced non-small-cell lung cancer who have high PD-L1 expression (≥50%).

The study expects that the combination treatment will lead to a lower risk of early disease progression and a higher objective tumor response, providing insights into long-term benefits for patients not eligible for other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line pembrolizumab with or without platinum doublet chemotherapy in non-small-cell lung cancer patients with PD-L1 expression ≥50. Descourt, R., Chouaid, C., Pérol, M., et al.[2021]

In a phase II trial involving 15 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant treatment with pembrolizumab showed a major pathologic response in 27% of patients, indicating promising antitumor activity before surgery.

The treatment was found to be feasible and safe, with only 33% of patients experiencing moderate adverse events, and no postoperative mortality, suggesting that pembrolizumab does not compromise surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Eichhorn, F., Klotz, LV., Kriegsmann, M., et al.[2022]

In a real-life study of 108 patients with advanced non-small cell lung cancer (NSCLC) and a PD-L1 tumor proportion score of ≥50%, pembrolizumab showed a median progression-free survival of 10.1 months, similar to results from the KEYNOTE-024 trial.

The treatment was generally well-tolerated, with only 8% of patients experiencing grade 3 adverse events, and no severe (grade 4 or 5) adverse events reported, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line pembrolizumab for non-small cell lung cancer patients with PD-L1 ≥50% in a multicenter real-life cohort: The PEMBREIZH study. Amrane, K., Geier, M., Corre, R., et al.[2021]

Pembrolizumab, a PD-1 inhibitor, has demonstrated clinical effectiveness in treating various solid tumors, particularly in patients with PD-L1-positive non-small-cell lung cancer and unresectable/metastatic melanoma.

Early-phase trials and ongoing studies are focused on further confirming the clinical benefits of pembrolizumab in thoracic malignancies, highlighting its potential as a significant treatment option in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. Karim, S., Leighl, N.[2017]

In a clinical trial, the combination of the PD-1 inhibitor pembrolizumab with chemotherapy showed a significant improvement in overall survival for patients with newly diagnosed advanced non-squamous non-small cell lung cancer, with a 12-month survival rate of 69.2%.

This survival rate was notably higher compared to the 49.4% survival rate in patients who received chemotherapy alone, indicating that pembrolizumab may enhance the effectiveness of standard chemotherapy in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Combo Therapy for Lung Cancer Extends Survival. [2019]

Immune checkpoint inhibitors, such as Pembrolizumab, Nivolumab, and Atezolizumab, have significantly improved treatment outcomes for advanced nonsmall cell lung cancer (NSCLC), especially for patients who have progressed after chemotherapy.

A new patient-oriented algorithm has been developed to help clinicians choose the most effective and personalized treatment options for advanced NSCLC, aiming to enhance patient quality of life and survival rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current uses of check inhibitors in the fight against advanced and/or metastatic lung cancer: will immunotherapy overcome chemotherapy? Cetin, B., Bilgetekin, İ., Ozet, A.[2020]

In a study involving 1034 patients with previously treated, PD-L1-positive advanced non-small-cell lung cancer, pembrolizumab significantly improved overall survival compared to docetaxel, with median survival times of 12.7 months for pembrolizumab 10 mg/kg versus 8.5 months for docetaxel.

Pembrolizumab also demonstrated a favorable safety profile, with fewer grade 3-5 treatment-related adverse events (13% for 2 mg/kg and 16% for 10 mg/kg) compared to docetaxel (35%), making it a promising treatment option for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Herbst, RS., Baas, P., Kim, DW., et al.[2022]

Citations

1. sciencedirect.com sciencedirect.com/science/article/pii/S0959804925000826

Real-world effectiveness and tolerability of sotorasib in ... This study gave insights into effectiveness and safety of sotorasib in a real-world setting, in advanced or metastatic KRAS G12C-mutated non-squamous NSCLC.

2. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39970524/

Real-world effectiveness and tolerability of sotorasib in ... This study gave insights into effectiveness and safety of sotorasib in a real-world setting, in advanced or metastatic KRAS G12C-mutated non-squamous NSCLC.

3. nature.com nature.com/articles/s41591-025-03732-5

Molecular determinants of sotorasib clinical efficacy in ... Molecular determinants of KRAS(G12C)inhibitor efficacy in KRASG12C-mutated non-small-cell lung cancer (NSCLC) remain poorly characterized.

4. lungcancerjournal.info lungcancerjournal.info/article/S0169-5002(24)00494-X/fulltext

Real-world comparative effectiveness of sotorasib versus ... First study comparing real-world effectiveness of sotorasib vs. docetaxel treatment. Median OS was longer with sotorasib vs. docetaxel (2L HR=0.62; 2L+HR=0.65).

5. ascopubs.org ascopubs.org/doi/abs/10.1200/JCO.22.02524

2-Year Analysis of CodeBreaK 100 Sotorasib produced an ORR of 41%, median duration of response of 12.3 months, progression-free survival (PFS) of 6.3 months, overall survival (OS) of 12.5 ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12566659/

Sex-Related Safety Signals of Sotorasib in Non-Small Cell ... A total of 456 adverse events were collected, among which diarrhea (n = 155), non-small cell lung cancer (n = 134), metastatic non-small cell ...

7. academic.oup.com academic.oup.com/oncolo/article/30/1/oyae356/7976610

Pooled safety analysis and management of sotorasib-related ... Sotorasib has a well-characterized safety profile in patients with KRAS G12C-mutated advanced NSCLC, and key risks are manageable with dose ...

8. lumakrashcp.com lumakrashcp.com/

LUMAKRAS® (sotorasib): KRAS G12C-Mutated NSCLC ... LUMAKRAS is indicated for the treatment of adult patients with KRAS G12C-mutated locally advanced or metastatic non-small cell lung cancer (NSCLC).

9. annalsofoncology.org annalsofoncology.org/article/S0923-7534(22)02967-2/fulltext

989P Sotorasib in advanced KRAS p.G12C-mutated non- ... The study was primarily designed to assess the safety of sotorasib 960 mg QD. Real-world progression-free survival (rwPFS) was estimated for study-436 (allowed ...