Adagrasib + Pembrolizumab for Non-Small Cell Lung Cancer

Recruiting at 585 trial locations

Overseen By BMS Clinical Trials Contact Center www.BMSClinicalTrials.com

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Mirati Therapeutics Inc.

Must not be taking: QTc prolonging drugs, KRAS inhibitors

Disqualifiers: Autoimmune, Cardiovascular, Bone marrow, others

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: 12 weeks

630 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment combination for non-small cell lung cancer (NSCLC) with a specific gene mutation called KRAS G12C. The study aims to evaluate the effectiveness of combining adagrasib (a targeted therapy) and pembrolizumab (an immunotherapy) with standard chemotherapy, compared to a placebo with the same chemotherapy. Participants should have advanced NSCLC that has not been treated with systemic anti-cancer therapies and must have a KRAS G12C mutation. This trial suits individuals with this type of lung cancer who have not received other treatments. As a Phase 3 trial, it represents the final step before FDA approval, offering participants a chance to contribute to potentially groundbreaking treatment advancements.

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

The trial protocol does not specify if you need to stop taking your current medications, but it mentions that ongoing treatment with medications known to cause prolonged QTc interval must be switched to an alternative before joining the study.

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

Research has shown that adagrasib, a treatment under investigation for non-small cell lung cancer (NSCLC), has been studied for its safety. In earlier studies, most patients (97.4%) experienced side effects. About half of these side effects were mild to moderate, while nearly half were more severe. There were also two cases of very serious side effects.

Adagrasib is being tested in combination with pembrolizumab and chemotherapy. Pembrolizumab has FDA approval for other conditions, indicating it is safe for use in people, though it can still cause side effects.

Overall, while adagrasib appears promising, it carries risks. The trial under consideration is in a later stage, providing some existing safety information, but it is not yet complete. It is important to discuss potential risks and benefits with a doctor before deciding to join a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Adagrasib for treating non-small cell lung cancer because it targets a specific mutation in the KRAS gene, which is a common driver of this cancer. Unlike traditional chemotherapy, which attacks all rapidly dividing cells, Adagrasib specifically disrupts cancer cell growth by inhibiting this mutation. When combined with Pembrolizumab, an immune checkpoint inhibitor, it could enhance the immune system's ability to fight cancer more effectively. This targeted approach may offer a more personalized treatment option with potentially fewer side effects compared to conventional therapies.

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

Research has shown that using adagrasib with pembrolizumab may be promising for treating non-small cell lung cancer (NSCLC) with the KRAS G12C mutation. In this trial, some participants will receive adagrasib, while others will receive a placebo. Studies have found that this combination can extend patients' lives, with an average survival time of 18.3 months. After one year, nearly half of the patients had not experienced cancer progression. This treatment also proved effective for patients whose cancer had spread to the brain. Overall, adagrasib with pembrolizumab could offer a new option for people with this specific type of lung cancer. ^{2 5 6 7 8}

Are You a Good Fit for This Trial?

This trial is for adults with advanced non-squamous non-small cell lung cancer that has a specific mutation (KRAS G12C) and haven't been treated before. Participants should be fit enough for chemotherapy, but those with certain health conditions or previous treatments are excluded.

Inclusion Criteria

My non-squamous NSCLC has a KRAS G12C mutation.

I have brain metastases smaller than 20 mm and don't need immediate treatment.

My cancer can be measured on scans.

Exclusion Criteria

Other protocol-defined Inclusion/Exclusion criteria apply

I haven't had serious heart problems in the last 6 months.

I have been treated with drugs targeting the KRAS G12C mutation.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive adagrasib plus pembrolizumab plus platinum-doublet chemotherapy or placebo plus pembrolizumab plus platinum-doublet chemotherapy

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Adagrasib
• Pembrolizumab
• Platinum-doublet Chemotherapy

Trial Overview The study tests if adding Adagrasib to the standard treatment of Pembrolizumab plus platinum-based chemo (like Cisplatin or Carboplatin) is better than using a placebo with the standard treatment in patients with this type of lung cancer.

How Is the Trial Designed?

Group I: Adagrasib Experimental Treatment 5 Interventions

Group II: Placebo Placebo Group 5 Interventions

Who Is Running the Clinical Trial?

Mirati Therapeutics Inc.

Lead Sponsor

Trials

73

Recruited

8,900+

Dr. Charles M. Baum

Mirati Therapeutics Inc.

Chief Executive Officer since 2023

MD, PhD

Dr. Joseph Leveque

Mirati Therapeutics Inc.

Chief Medical Officer since 2021

MD

Published Research Related to This Trial

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, an anti-PD-1 antibody, has been approved for treating unresectable or metastatic melanoma, especially in patients who have progressed after ipilimumab treatment, marking a significant advancement in immuno-oncology.

The drug has also received breakthrough status for treating non-small cell lung cancer (NSCLC) that is EGFR mutation-negative and ALK rearrangement-negative, indicating its broad potential in cancer therapy, with ongoing trials to explore its use in various tumor types.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab. Khoja, L., Butler, MO., Kang, SP., et al.[2022]

Adagrasib combined with pembrolizumab shows promising efficacy for patients with newly diagnosed non-small cell lung cancer with a KRASG12C mutation, achieving overall response rates of 49% and 57% in two separate trials.

This drug combination demonstrated a favorable safety profile, exhibiting lower liver toxicity compared to other combinations of checkpoint inhibitors and targeted therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Frontline Promise for Adagrasib-Pembrolizumab Combination. [2023]

The PePS2 trial demonstrated that pembrolizumab can be safely administered to patients with non-small-cell lung cancer (NSCLC) and a performance status of 2, with a toxicity rate of 28% and no severe treatment-related adverse events, indicating a manageable safety profile.

Efficacy outcomes showed that 38% of first-line and 36% of subsequent-line patients experienced durable clinical benefit, with higher response rates correlating with tumor proportion scores, suggesting that pembrolizumab is effective for this underserved patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in patients with non-small-cell lung cancer of performance status 2 (PePS2): a single arm, phase 2 trial. Middleton, G., Brock, K., Savage, J., et al.[2020]

In a study of 145 patients with PD-L1 strongly positive non-small-cell lung cancer (NSCLC), those with higher PD-L1 expression (≥ 75%) experienced better treatment outcomes with pembrolizumab, showing a higher objective response rate (51% vs. 33%) and longer progression-free survival (13.9 months vs. 5.2 months).

Patients with liver metastasis had significantly poorer responses to pembrolizumab, with an objective response rate of only 20% compared to 47% in those without liver metastasis, indicating that both PD-L1 expression and liver metastasis are important predictors of treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Differential Efficacy of Pembrolizumab According to Metastatic Sites in Patients With PD-L1 Strongly Positive (TPS ≥ 50%) NSCLC. Takeyasu, Y., Yoshida, T., Shibaki, R., et al.[2021]

In a study of 72 treatment-naïve patients with advanced non-small cell lung cancer (NSCLC) and high PD-L1 expression, pembrolizumab showed an objective response rate of 45.8%, with even higher rates of 70.0% in patients with pre-existing interstitial lung disease (ILD).

Patients with ILD had similar overall survival rates compared to those without ILD, suggesting that pembrolizumab can be safely administered to NSCLC patients with ILD without compromising their prognosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pre-existing interstitial lung disease does not affect prognosis in non-small cell lung cancer patients with PD-L1 expression ≥50% on first-line pembrolizumab. Yamaguchi, O., Kaira, K., Shinomiya, S., et al.[2021]

Pembrolizumab, when combined with carboplatin and pemetrexed, significantly improves overall and progression-free survival rates in patients with non-small cell lung cancer (NSCLC), demonstrating its efficacy as a treatment option.

This case report highlights a unique instance of immune-mediated sarcoidosis developing in a patient with NSCLC after receiving pembrolizumab, indicating potential immune-related side effects of this therapy that require further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pulmonary Sarcoidosis Activation following Neoadjuvant Pembrolizumab plus Chemotherapy Combination Therapy in a Patient with Non-Small Cell Lung Cancer: A Case Report. Fakhri, G., Akel, R., Salem, Z., et al.[2022]

In a pooled analysis of 444 patients with PD-L1-negative advanced/metastatic non-small cell lung cancer (NSCLC), pembrolizumab combined with chemotherapy significantly improved overall survival (hazard ratio 0.63) and progression-free survival (hazard ratio 0.68) compared to chemotherapy alone.

Despite high rates of adverse events (99.2% in the pembrolizumab group), the combination therapy was manageable and resulted in an impressive objective response rate of 87.5% and a 3-year overall survival rate of 100% for patients completing 2 years of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab plus chemotherapy versus chemotherapy alone in patients with advanced non-small cell lung cancer without tumor PD-L1 expression: A pooled analysis of 3 randomized controlled trials. Borghaei, H., Langer, CJ., Paz-Ares, L., et al.[2021]

Citations

1. nejm.org nejm.org/doi/full/10.1056/NEJMoa2204619

Adagrasib in Non–Small-Cell Lung Cancer Harboring a ... Treatment-related adverse events occurred in 97.4% of the patients — grade 1 or 2 in 52.6% and grade 3 or higher in 44.8% (including two grade 5 ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11534526/

Adagrasib in KRYSTAL-12 has Broken the KRASG12C ... The Phase III KRYSTAL-12 trial demonstrated that adagrasib significantly improved median progression-free survival (mPFS) compared with ...

3. cancernetwork.com cancernetwork.com/view/adagrasib-pembrolizumab-yields-improved-survival-in-kras-g12c-mutated-nsclc

Adagrasib/Pembrolizumab Yields Improved Survival in ... At 12 months, the PFS rate was 48%, and at 18 months it was 38%. The median overall survival (OS) was 18.3 months (95% CI, 14.3-not evaluable [ ...

4. actr.amegroups.org actr.amegroups.org/article/view/9710/html

Intracranial efficacy of adagrasib in patients with KRAS G12C ... Adagrasib monotherapy in this cohort of NSCLC patients with untreated CNS metastases demonstrated an intracranial (IC) objective response rate ( ...

5. asco.org asco.org/abstracts-presentations/ABSTRACT485936

First-line adagrasib (ADA) with pembrolizumab (PEMBRO) ... First-line ADA plus PEMBRO demonstrated promising clinical efficacy and a manageable safety profile, regardless of PD-L1 status.

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.e20648

Clinical outcomes and safety profile of adagrasib in KRAS ... Adagrasib showed a median overall survival (OS) of 14.74 months (95% CI: 12.06–17.42, I² = 40.4%) and progression-free survival (PFS) of 6.80 ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10860949/

Safety and Intracranial Activity of Adagrasib in Patients With ... The median IC duration of response (DOR) was 12.7 months, the median IC progression-free survival (PFS) was 5.4 months, and the median overall ...

8. thelancet.com thelancet.com/journals/lancet/article/PIIS0140-6736(25)00866-9/abstract

mutated non-small-cell lung cancer (KRYSTAL-12): a ... Grade 3 and above treatment-related adverse events occurred in 140 (47%) of 298 patients treated with adagrasib and 64 (46%) of 140 with ...