Defactinib + Avutometinib + Nivolumab for Lung Cancer

Recruiting at 2 trial locations

Overseen By Mashunte Holmes, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Emory University

Must not be taking: Warfarin, Strong CYP3A4

Disqualifiers: Auto-immune conditions, Brain metastasis, Hepatitis, others

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

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

Compensation: Varies

Number of Visits: Unknown

Duration: 6 months

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a new combination of drugs to treat a specific type of lung cancer that hasn't responded well to standard treatments. The study uses two kinase inhibitors, defactinib and avutometinib, along with nivolumab, an immunotherapy drug, to determine if they can better target and kill cancer cells. The trial targets individuals with advanced non-small cell lung cancer with an LKB1 mutation who have not responded to previous treatments. Those diagnosed with this type of lung cancer and who have experienced limited success with other treatments might find this trial suitable. As a Phase 2 trial, the research measures the treatment's effectiveness in an initial, smaller group, offering a chance to benefit from potentially effective new therapies.

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

The trial protocol does not specify if you must stop all current medications. However, you cannot have had systemic therapy within 3 weeks before the study, and you must avoid medications that interact with defactinib, such as strong CYP3A4 or CYP2C9 inhibitors or inducers, and strong P-glycoprotein inhibitors or inducers. If you're on warfarin, you need to switch to low-molecular-weight heparin or direct oral anticoagulants.

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

Research shows that the combination of defactinib, avutometinib, and nivolumab is generally well-tolerated. Studies have found that defactinib and avutometinib, both kinase inhibitors, have been tested in various trials with promising safety results. Earlier studies demonstrated avutometinib's anti-tumor effects, and defactinib showed acceptable safety in patients with different tumor types.

In a previous trial, the combination of avutometinib and defactinib was administered on an intermittent schedule, meaning the treatment was not continuous. This trial reported that most patients experienced mild side effects. Nivolumab, an immunotherapy drug, is already approved for other conditions and is known to be safe for many patients. Overall, this combination aims to effectively target tumor cells while maintaining safety for clinical use. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of defactinib, avutometinib, and nivolumab for lung cancer because it targets the disease in a unique way. Unlike standard chemotherapy, which attacks rapidly dividing cells generally, this combination includes a MEK inhibitor (avutometinib) and a FAK inhibitor (defactinib), which work together to disrupt specific cancer cell signaling pathways. Nivolumab, an immunotherapy, helps the immune system recognize and fight cancer cells more effectively. This multi-pronged approach could offer a more precise attack on lung cancer, potentially improving outcomes for patients who don’t respond well to existing treatments.

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

This trial will evaluate the combination of defactinib, avutometinib, and nivolumab for patients with non-small cell lung cancer (NSCLC). Studies have shown that this combination can be promising. In previous research, about 29 out of 100 patients experienced tumor shrinkage or disappearance with this treatment. On average, the treatment was effective for about 8.3 months. Patients lived an average of 14.5 months after starting the treatment and remained without cancer progression for about 5.7 months. These findings suggest that this treatment can effectively target certain cancer mutations and enhance the body's immune response against the cancer. ^{2 3 5 6 7}

Who Is on the Research Team?

Conor Steuer

Principal Investigator

Emory University Hospital/Winship Cancer Institute

Are You a Good Fit for This Trial?

This trial is for patients with advanced non-small cell lung cancer that has LKB1 mutation and hasn't responded to anti-PD1 treatments. It's aimed at those whose cancer may have spread, and who are looking for new treatment options.

Inclusion Criteria

My cancer has a known LKB1 mutation.

Absolute neutrophil count ≥ 1,500/mcL

Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for the institution; patients with Gilbert syndrome may enroll if total bilirubin < 3.0 mg/dL (51 umole/L)

Exclusion Criteria

History of allergic reactions attributed to compounds of similar chemical or biologic composition to avutometinib or defactinib

I have had a skin condition treated with medication in the past year, but early stage skin cancers removed by surgery are okay.

I haven't had any cancer except for ones fully treated or unlikely to come back in the last 2 years.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive defactinib orally twice daily, avutometinib twice weekly, and nivolumab intravenously on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

6 months

Monthly visits for treatment and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up every 3 months for up to 5 years.

5 years

Quarterly visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Avutometinib
• Defactinib
• Nivolumab

Trial Overview The trial tests a combination of defactinib and avutometinib (kinase inhibitors) with nivolumab (an immunotherapy drug). The goal is to see if this mix can better kill tumor cells in patients resistant to previous anti-PD1 therapy.

How Is the Trial Designed?

Group I: Treatment (defactinib, avutometinib, nivolumab) Experimental Treatment 7 Interventions

Patients receive defactinib PO BID on days 1-21, avutometinib PO twice weekly on Monday and Thursday, Tuesday and Friday or Wednesday and Saturday for 21 days and nivolumab IV on day 1. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo biopsy, blood sample collection, CT or PET on study.

Who Is Running the Clinical Trial?

Emory University

Lead Sponsor

Trials

1,735

Recruited

2,605,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

In the Asian subpopulation with advanced non-small cell lung cancer (NSCLC) and PD-L1 expression ≥1%, patients treated with nivolumab plus ipilimumab showed significantly improved overall survival (OS) and progression-free survival (PFS) compared to those receiving chemotherapy, with a 3-year OS rate of 53% versus 37%.

The safety profile of nivolumab plus ipilimumab was manageable, with grade 3-4 treatment-related adverse events occurring in 40% of patients, similar to the 36% in the chemotherapy group, indicating no new safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line nivolumab + ipilimumab in advanced NSCLC: CheckMate 227 subpopulation analyses in Asian patients. O'Byrne, KJ., Lee, KH., Kim, SW., et al.[2022]

Nivolumab, a PD-1 inhibitor, has shown significant efficacy and a favorable safety profile in treating non-small cell lung cancer (NSCLC), indicating its potential as a key immunotherapy option.

Despite its benefits, there are still important questions regarding patient selection, optimal treatment timing, management of side effects, and overcoming immunoresistance that need to be addressed for better clinical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Focus on Nivolumab in NSCLC. Cortinovis, DL., Canova, S., Abbate, M., et al.[2021]

The study compared PD-L1 expression in 100 non-small cell lung cancer samples using two different assays (22C3 and SP263) and found that the agreement rates between the assays were high, ranging from 88% to 97% at various cut-offs.

There was no significant difference in tumor proportion scores between the two assays, indicating that the Ventana SP263 assay can be reliably used instead of the 22C3 assay for guiding treatment decisions with PD-1 inhibitors like nivolumab and pembrolizumab.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of PD-L1 Assays in Non-small Cell Lung Cancer: 22C3 pharmDx and SP263. Fujimoto, D., Yamashita, D., Fukuoka, J., et al.[2019]

The phase III CheckMate-227 trial indicates that the combination of ipilimumab and nivolumab significantly improves progression-free survival in non-small cell lung cancer patients with a high tumor mutation burden, with 43% of patients remaining progression-free after 1 year.

In contrast, only 13% of patients treated with chemotherapy experienced progression-free survival, highlighting the potential efficacy of the checkpoint inhibitor combination over traditional chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High TMB Predicts Immunotherapy Benefit. [2019]

The combination of nivolumab and ipilimumab has shown promise as a first-line treatment for previously untreated advanced non-small-cell lung cancer, as demonstrated in the Phase III CheckMate 227 study.

This study is significant because it is the first to evaluate a chemotherapy-sparing approach using dual immune checkpoint inhibition, while also considering tumor mutational burden as a biomarker for selecting suitable patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus ipilimumab in non-small-cell lung cancer. Reck, M., Borghaei, H., O'Byrne, KJ.[2019]

Nivolumab plus ipilimumab showed durable and long-term efficacy in treating advanced non-small cell lung cancer (NSCLC) compared to chemotherapy, regardless of tumor PD-L1 expression levels.

These findings are based on updated results from part 1 of the phase 3 CheckMate 227 trial, indicating that this combination therapy could be a more effective frontline treatment option for NSCLC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab/Ipilimumab Combo Yields Durable Efficacy in Advanced NSCLC. Kahl, KL.[2021]

Nivolumab, an immune checkpoint inhibitor, significantly improves overall survival and progression-free survival in patients with advanced stage squamous cell non-small cell lung cancer (NSCLC) compared to docetaxel, as shown in the CHECKMATE 017 study.

The safety and tolerability of nivolumab are favorable, and interestingly, the expression of the PD-L1 ligand does not predict treatment outcomes, suggesting that other factors may influence the effectiveness of this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab in the treatment of metastatic squamous non-small cell lung cancer: a review of the evidence. Lim, JS., Soo, RA.[2018]

The FDA approved nivolumab combined with ipilimumab and chemotherapy as a first-line treatment for metastatic or recurrent non-small cell lung cancer (NSCLC), based on a study involving 719 patients that showed improved overall survival (OS) of 14.1 months compared to 10.7 months for chemotherapy alone.

Patients receiving the combination treatment also experienced better progression-free survival and overall response rates, indicating that this combination therapy is more effective than traditional chemotherapy alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Nivolumab with Ipilimumab and Chemotherapy for Metastatic Non-small Cell Lung Cancer, A Collaborative Project Orbis Review. Vellanki, PJ., Mulkey, F., Jaigirdar, AA., et al.[2022]

The combination of afatinib and nimotuzumab showed an acceptable safety profile in 50 advanced non-small cell lung cancer patients, with 16% experiencing grade 3 toxicities, primarily skin rash and diarrhea.

This treatment resulted in a 23% overall response rate, with a median progression-free survival of 4.0 months and overall survival of 11.7 months, indicating promising antitumor activity in patients resistant to previous therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase Ib/II Study of Afatinib in Combination with Nimotuzumab in Non-Small Cell Lung Cancer Patients with Acquired Resistance to Gefitinib or Erlotinib. Lee, JY., Sun, JM., Lim, SH., et al.[2018]

Nivolumab (Opdivo) monotherapy led to complete regression of local recurrence and multiple lung metastases in a patient with recurrent skin melanoma and a positive BRAF mutation, demonstrating its efficacy as a treatment option.

After 5 courses of nivolumab, the patient experienced significant improvement in her condition, achieving an ECOG performance status of 0, indicating a return to an active lifestyle without pain, and normal serum LDH levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[EVALUATION OF THE EFFICASY OF THE DRUG OPDIVO (NIVOLUMAB) IN A PATIENT DIAGNOSED WITH UNRESECTABLE SKIN MELANOMA, POSITIVE BRAF MUTATION AND DISEASE DISSEMINATION (CASE REPORT)]. Samsonia, M., Kandelaki, M., Gibradze, O., et al.[2021]

In a pooled analysis of 1332 patients with advanced non-small-cell lung cancer (NSCLC), the combination of nivolumab and ipilimumab showed a median overall survival (OS) of 18.6 months and a 3-year OS rate of 35%, indicating significant long-term survival benefits compared to traditional chemotherapy.

The study found that patients who responded to treatment at 6 months had markedly better survival rates, with a 3-year OS of 66% for responders, highlighting the importance of early response in predicting long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term survival with first-line nivolumab plus ipilimumab in patients with advanced non-small-cell lung cancer: a pooled analysis. Borghaei, H., Ciuleanu, TE., Lee, JS., et al.[2023]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT06495125

NCT06495125 | Defactinib, Avutometinib and Nivolumab ... Giving defactinib and avutometinib in combination with nivolumab may kill more tumor cells in patients with anti-PD1 refractory LKB1-mutant advanced non-small ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12423438/

Emerging Targets in Non-Small Cell Lung Cancer - PMC It achieved an ORR of 28.6%, mDOR of 8.3 months, mOS of 14.5 months and mPFS of 5.7 months in a phase II trial (NCT03539536) including patients ...

3. ascopubs.org ascopubs.org/doi/10.1200/JCO.2021.39.15_suppl.TPS9588

Clinical trial in progress: Phase II trial of defactinib (VS- ... Background: Despite successful treatment of primary uveal melanomas (UM), up to 50% of patients subsequently develop systemic metastasis, ...

4. conference-correspondent.com conference-correspondent.com/highlights/aacr/aacr-asco-2021-midyear-review/phase-1-trial-of-vs-6766-a-dual-raf-mek-inhibitor-and-defactinib-an-fak-inhibitor

Phase 1 Trial of VS-6766, a Dual RAF-MEK Inhibitor, and ... A phase I trial of the combination of the dual RAF-MEK inhibitor VS-6766 and the FAK inhibitor defactinib: evaluation of efficacy in KRAS mutated NSCLC.

5. mdpi.com mdpi.com/2072-6694/15/11/2899

Emerging Targeted Therapies in Advanced Non-Small-Cell ... Targeted therapy is an effective treatment that has significantly improved survival in NSCLC patients with actionable mutations. However, therapy resistance ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT06495125

NCT06495125 | Defactinib, Avutometinib and Nivolumab ... Giving defactinib and avutometinib in combination with nivolumab may kill more tumor cells in patients with anti-PD1 refractory LKB1-mutant advanced non-small ...

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2025/219616Orig1s000MultidisciplineR.pdf

219616Orig1s000 - accessdata.fda.gov RAMP-201 (NCT04625270) is a randomized, multicenter trial assessing the combination of avutometinib and defactinib versus avutometinib ...