Divarasib + Pembrolizumab for Non-Small Cell Lung Cancer

(KRAScendo 170 Trial)

Recruiting at 109 trial locations

Overseen By Reference Study ID Number: BO44426 https://forpatients.roche.com/

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Hoffmann-La Roche

Must not be taking: KRAS inhibitors

Disqualifiers: Squamous NSCLC, CNS metastases, others

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

Compensation: Varies

Number of Visits: 3

Duration: Up to approximately 3 years

320 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new treatment combination for individuals with advanced or metastatic non-small cell lung cancer (NSCLC), using two drugs: divarasib (GDC-6036) and pembrolizumab. The trial aims to assess the safety of this combination, how the body processes these drugs, and their effectiveness together. Participants will receive varying doses of divarasib combined with pembrolizumab, and some may also receive chemotherapy. This trial suits those diagnosed with advanced or metastatic NSCLC who have not yet undergone treatment. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive this new combination therapy.

Will I have to stop taking my current medications?

The trial information does not specify whether 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 shows that divarasib, when used alone, has a manageable safety profile, meaning most side effects can be effectively handled. In studies with 137 patients, including those with non-small cell lung cancer (NSCLC), divarasib was generally well-tolerated. Common side effects were mild, such as fatigue and nausea.

Pembrolizumab, another part of this study, is already approved for use in various cancers and has a well-known safety profile. Common side effects include fatigue, itching, and rash, while serious side effects are rare but possible.

The researchers aim to determine if combining divarasib with pembrolizumab works well without increasing side effects. So far, earlier findings suggest the combination is promising for safety. However, this study will provide a deeper understanding. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of divarasib and pembrolizumab for non-small cell lung cancer because it introduces a novel approach to treatment. Unlike existing therapies, which often rely on chemotherapy or targeted drugs aimed at specific mutations, divarasib targets the KRAS mutation, a common but challenging target in lung cancer. When combined with pembrolizumab, an immunotherapy drug that unleashes the body's immune system against cancer cells, this treatment has the potential to offer a more effective and personalized approach. This combination could enhance the immune response and improve outcomes beyond what current treatments achieve.

What evidence suggests that this trial's treatments could be effective for non-small cell lung cancer?

Research has shown that divarasib, when used alone, may help treat certain cancers, particularly those with a KRAS G12C mutation. This mutation often appears in non-small cell lung cancer (NSCLC). Divarasib specifically targets and blocks this mutation, potentially stopping cancer cell growth. Early studies indicate that it is generally safe and shows promise in shrinking tumors. In this trial, participants will receive divarasib combined with pembrolizumab, an immunotherapy that has already succeeded in treating NSCLC by helping the immune system fight cancer cells. Combining divarasib with pembrolizumab might enhance treatment effectiveness by attacking the cancer in different ways. ^{2 3 5 6 7}

Who Is on the Research Team?

Clinical Trials

Principal Investigator

Hoffmann-La Roche

Are You a Good Fit for This Trial?

This trial is for adults with advanced or metastatic non-small cell lung cancer (NSCLC) that hasn't been treated yet and has a specific mutation called KRAS G12C. Participants need to have measurable disease, be in good physical condition (ECOG 0 or 1), and provide tumor tissue samples. They can't join if they've had another cancer within the last 5 years, untreated brain metastases, uncontrolled symptoms from their cancer, prior treatment with KRAS G12C inhibitors, certain lung conditions, active infections like TB, or recent heart problems.

Inclusion Criteria

My condition has the required biomarker.

I am fully active or can carry out light work.

I can provide a sample of my tumor in the required format for the study.

Exclusion Criteria

Known hypersensitivity to any of the components of divarasib or pembrolizumab; or known hypersensitivity to pemetrexed, carboplatin, or cisplatin (Cohort B only)

I have not had serious lung or heart issues in the last 3 months.

My lung cancer is of the squamous cell type.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive divarasib in combination with pembrolizumab and potentially chemotherapy, with dose finding and expansion stages

Up to approximately 3 years

Every 3 weeks (in-person for IV infusions)

Follow-up

Participants are monitored for safety, pharmacokinetics, and activity after treatment

Up to approximately 3 years

What Are the Treatments Tested in This Trial?

Interventions

• GDC-6036
• Pembrolizumab

Trial Overview

The study tests Divarasib combined with other anti-cancer drugs: Pemetrexed, Cisplatin/Carboplatin and Pembrolizumab in patients who haven’t received any previous treatments for their NSCLC. It aims to assess how safe this combination is and how it affects the body (pharmacokinetics) as well as its effectiveness against the cancer.

How Is the Trial Designed?

Group I: Cohort D - Dose Expansion Experimental Treatment 1 Intervention

Participants enrolled in this cohort will receive one dose level of divarasib QD.

Group II: Cohort C - Dose Expansion Experimental Treatment 1 Intervention

Participants enrolled in this cohort will receive one dose level of divarasib QD.

Group III: Cohort B - Combination Dose Finding + Dose Expansion Experimental Treatment 5 Interventions

Participants enrolled in this cohort will receive divarasib (different dose levels will be evaluated) QD combined with pembrolizumab 200 mg IV Q3W plus investigator's choice of platinum-based chemotherapy (carboplatin or cisplatin) and pemetrexed.

Group IV: Cohort A - Combination Dose Finding + Dose Expansion Experimental Treatment 2 Interventions

Participants will be enrolled in different cohorts to receive divarasib (different dose levels will be evaluated) once a day (QD) combined with pembrolizumab 200 mg intravenous (IV) infusion every 3 weeks (Q3W). During the expansion stage, some participants are planned to be randomized to one divarasib combination dose level; other participants are planned to be randomized to another divarasib combination dose level. Divarasib will be given in combination with pembrolizumab.

Who Is Running the Clinical Trial?

Hoffmann-La Roche

Lead Sponsor

Trials

2,482

Recruited

1,107,000+

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Avastin, Herceptin, Rituxan, Accu-Chek

Dr. Levi Garraway

Hoffmann-La Roche

Chief Medical Officer since 2019

MD from the University of Basel

Dr. Thomas Schinecker

Hoffmann-La Roche

Chief Executive Officer since 2023

PhD in Molecular Biology from New York University

Published Research Related to This Trial

Pembrolizumab, a PD-1 inhibitor used in cancer treatment, can lead to rare but serious immune-related adverse events, including type 1 diabetes mellitus, occurring in about 0.2% of cases.

A review of 42 cases revealed that patients may develop diabetic ketoacidosis during treatment, highlighting the need for blood glucose monitoring and awareness of this potential side effect among clinicians.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Programmed Cell Death-1 Inhibitor-Induced Type 1 Diabetes Mellitus. Clotman, K., Janssens, K., Specenier, P., 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 monoclonal antibody targeting PD-1, showed significant efficacy in treating a 79-year-old patient with advanced squamous cell lung cancer, leading to a complete response after just 3 cycles of treatment.

However, the patient developed acute myelomonocytic leukemia after starting pembrolizumab, highlighting a potential safety concern that warrants further investigation into the drug's effects on blood cell production.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Acute myelomonocytic leukemia during pembrolizumab treatment for non-small cell lung cancer: A case report. Kim, HB., Park, SG., Hong, R., et al.[2020]

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 Phase 2 study involving 35 patients with non-small cell lung cancer, neoadjuvant pembrolizumab was found to be safe and well tolerated, with only one surgery delay due to thyroiditis and no mortality within 90 days post-surgery.

The study showed a high rate of R0 resection (88%) and a major pathologic response in 28% of patients, indicating that pembrolizumab may be more effective than standard neoadjuvant chemotherapy in this setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Perioperative outcomes of pulmonary resection after neoadjuvant pembrolizumab in patients with non-small cell lung cancer. Tong, BC., Gu, L., Wang, X., et al.[2022]

Pembrolizumab (Keytruda) was approved by the FDA for treating metastatic non-small cell lung cancer (mNSCLC) in patients with tumors expressing PD-L1, showing significant improvements in overall survival (OS) and progression-free survival (PFS) in two major clinical trials with thousands of participants.

In the KEYNOTE-024 trial, pembrolizumab demonstrated a 40% reduction in the risk of death compared to chemotherapy, while in the KEYNOTE-010 trial, it also showed a significant survival advantage over chemotherapy in patients who had previously progressed on treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for Treatment of Metastatic Non-Small Cell Lung Cancer: First-Line Therapy and Beyond. Pai-Scherf, L., Blumenthal, GM., Li, H., et al.[2022]

In a study involving 449 patients with advanced non-small-cell lung cancer (NSCLC), pembrolizumab showed overall response rates of 15% at 2 mg/kg, 25% at 10 mg/kg every 3 weeks, and 21% at 10 mg/kg every 2 weeks, indicating that the 2 mg/kg dose may be sufficient for efficacy.

The analysis revealed no significant relationship between the dose of pembrolizumab and its efficacy or safety, suggesting that the lower dose of 2 mg/kg every 3 weeks is effective and safe for patients with previously treated advanced NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Systematic evaluation of pembrolizumab dosing in patients with advanced non-small-cell lung cancer. Chatterjee, M., Turner, DC., Felip, E., et al.[2022]

Pembrolizumab is a safe and effective immune checkpoint inhibitor that targets the PD-1 receptor, currently approved for treating advanced melanoma and metastatic non-small cell lung cancer (NSCLC).

Ongoing studies are exploring the potential of pembrolizumab in combination with other treatments for lung cancer and other cancer types, while also investigating biomarkers that may predict patient response to this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of PD-L1 positive advanced or metastatic non-small cell lung cancer. Dang, TO., Ogunniyi, A., Barbee, MS., et al.[2020]

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]

Citations

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The purpose of this study is to evaluate the efficacy and safety of divarasib and pembrolizumab compared with pembrolizumab and pemetrexed and carboplatin or ...

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A study to compare divarasib plus pembrolizumab with standard

The purpose of this study is to evaluate the efficacy and safety of divarasib and pembrolizumab compared with pembrolizumab and pemetrexed and carboplatin or.

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NCT05789082 | A Study Evaluating the Safety, Activity, and ...

The purpose of this study is to evaluate the safety, pharmacokinetics (PK), and activity of divarasib combined with other anti-cancer therapies.

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A total of 137 patients (60 with non–small-cell lung cancer [NSCLC], 55 with colorectal cancer, and 22 with other solid tumors) received ...

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The purpose of this study is to evaluate the safety, pharmacokinetics (PK), and activity of divarasib combined with other anti-cancer therapies in participants ...

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Clinical trial for Non Small Cell Lung Carcinoma-Genentec...

This study aims to compare the effects of divarasib plus pembrolizumab versus standard first treatment (pembrolizumab plus chemotherapy) in people with NSCLC ...