Cabozantinib + Nivolumab for Lung Cancer

Recruiting at 739 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

Must not be taking: Anticoagulants, CYP3A4 inducers, Corticosteroids

Disqualifiers: Pregnancy, Cardiac disease, Autoimmune, 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

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

Compensation: Varies

Number of Visits: 24

Duration: 21-day cycles, ongoing until disease progression or unacceptable toxicity

117 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests new treatments for individuals with non-small cell lung cancer that has spread and is unresponsive to standard treatments. Researchers aim to determine if cabozantinib (also known as Cabometyx or Cometriq), alone or with nivolumab (Opdivo), is more effective than the usual chemotherapy. Cabozantinib inhibits tumor growth by blocking certain enzymes, while nivolumab enhances the immune system's ability to fight cancer. Individuals with non-small cell lung cancer that has progressed after initial chemotherapy and immunotherapy, and who lack specific gene mutations (such as EGFR or ALK), may be suitable candidates for this trial. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group of participants.

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. However, you must not be on certain medications like strong CYP3A4 inducers or continuous systemic corticosteroids above a certain dose. It's best to discuss your current medications with the trial team to ensure they don't interfere with the study.

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

Research has shown that cabozantinib has been tested for safety in people with kidney and thyroid cancer. In these studies, more than 25% of patients experienced common side effects like diarrhea and tiredness. Serious side effects, such as liver and stomach problems, occurred in less than 2% of patients.

When combined with nivolumab, another study found that serious side effects like diarrhea and pneumonia occurred in about 2% of patients, though these were not common. The combination also led to a few fatal reactions in a very small number of patients (less than 2%).

Both treatments are generally well-tolerated, but there is a risk of serious side effects. These results come from studies on different types of cancer, so it's important to consult a doctor to understand what this might mean for lung cancer patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about combining cabozantinib and nivolumab for lung cancer because it brings a novel approach to treatment. Unlike the standard chemotherapy options, which typically include drugs like docetaxel or paclitaxel, this combination targets cancer differently. Cabozantinib works by inhibiting certain proteins that promote tumor growth and spread, while nivolumab boosts the immune system's ability to fight cancer. This dual approach not only targets the tumor directly but also empowers the body's natural defenses, offering a potentially more effective and innovative treatment strategy for lung cancer.

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

Studies have shown that cabozantinib can slow lung cancer progression and may extend patients' lives. In some studies, about 43.3% of patients responded positively to cabozantinib, with their cancer not worsening for nearly 11 months on average. In this trial, one group of participants will receive cabozantinib alone, while another group will receive a combination of cabozantinib and nivolumab, a type of immunotherapy. Research indicates that this combination has effectively treated other cancers, like advanced kidney cancer, reducing the risk of death by 23% in those studies. These findings suggest that cabozantinib, either alone or with nivolumab, could be promising for treating non-small cell lung cancer. ^{6 7 8 9 10}

Who Is on the Research Team?

Joel W Neal

Principal Investigator

ECOG-ACRIN Cancer Research Group

Are You a Good Fit for This Trial?

This trial is for adults with non-squamous non-small cell lung cancer (NSCLC) who've had one round of platinum-based chemo and checkpoint inhibitor immunotherapy. They must have manageable side effects from past treatments, no major organ issues, can swallow pills, and have no severe heart conditions or untreated viral infections. Pregnant individuals or those planning to conceive are excluded.

Inclusion Criteria

I have previously received treatments like anti-VEGF, ipilimumab, or experimental drugs.

My doctor has documented the chemotherapy plan if I'm assigned to Arm C of the study.

My kidney function, measured by creatinine levels or clearance, is within the required range.

Exclusion Criteria

I do not have any heart, blood vessel, or clotting disorders.

I don't have any health issues that would make it unsafe for me to take cabozantinib and nivolumab.

I haven't taken certain medications recently.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Patients receive either cabozantinib alone, cabozantinib with nivolumab, or standard chemotherapy. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

21-day cycles, ongoing until disease progression or unacceptable toxicity

Visits every 21 days for treatment administration

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 3 years

Every 3 months

Correlative biomarker research

Correlative biomarker research will be performed on tissue and blood specimens collected within this trial.

What Are the Treatments Tested in This Trial?

Interventions

• Cabozantinib S-malate
• Nab-paclitaxel
• Nivolumab

Trial Overview The study tests if cabozantinib alone or combined with nivolumab is more effective than standard chemotherapy in NSCLC treatment. Cabozantinib blocks enzymes needed for tumor growth; nivolumab boosts the immune system's cancer fight. Standard chemo drugs kill or stop cancer cells from growing.

How Is the Trial Designed?

Group I: Step 2, Arm Z (cabozantinib S-malate, nivolumab) Experimental Treatment 5 Interventions

Patients in Step 2, Arm Z receive cabozantinib S-malate PO QD and nivolumab IV over 30 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may continue to receive therapy after investigator-assessed RECIST 1.1 defined progression, including stable clinical and performance status and have potential for continued clinical benefit. Patients also undergo ECHO as clinically indicated, CT throughout the trial, and collection of blood on study.

Group II: Step 1, Arm B (cabozantinib S-malate, nivolumab) Experimental Treatment 5 Interventions

Patients in Step 1, Arm B receive cabozantinib S-malate PO QD and nivolumab IV over 30 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may continue to receive therapy after investigator-assessed RECIST 1.1 defined progression, including stable clinical and performance status and have potential for continued clinical benefit. Patients also undergo ECHO as clinically indicated, CT throughout the trial, and collection of blood on study.

Group III: Step 1, Arm A (cabozantinib S-malate) Experimental Treatment 4 Interventions

Patients in Step 1, Arm A receive cabozantinib S-malate PO QD. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may continue to receive therapy after investigator-assessed RECIST 1.1 defined progression, including stable clinical and performance status and have potential for continued clinical benefit. Patients also undergo ECHO as clinically indicated, CT throughout the trial, and collection of blood on study.

Group IV: Step 1, Arm C (standard chemotherapy) Active Control 8 Interventions

Patients in Step 1, Arm C receive ramucirumab IV over 30-60 minutes and docetaxel IV over 1 hour on day 1, or docetaxel IV over 1 hour on days 1 and 8, or gemcitabine hydrochloride IV on days 1 and 8, or paclitaxel IV over 3 hours on day 1, or nab-paclitaxel IV over 30 minutes on days 1 and 8. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity and at the discretion of the treating physician. Patients also undergo ECHO as clinically indicated, CT throughout the trial, and collection of blood on study.

Cabozantinib S-malate is already approved in United States, European Union for the following indications:

Approved in United States as Cabometyx for:

• Advanced renal cell carcinoma (RCC)
• Hepatocellular carcinoma (HCC)
• Locally advanced or metastatic differentiated thyroid cancer (DTC)

Approved in United States as Cometriq for:

• Medullary thyroid cancer

Approved in European Union as Cabometyx for:

• Advanced renal cell carcinoma (RCC)
• Hepatocellular carcinoma (HCC)
• Locally advanced or metastatic differentiated thyroid cancer (DTC)

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

The combination of cabozantinib (a tyrosine kinase inhibitor) and nivolumab (an immune checkpoint inhibitor) significantly improved progression-free survival, overall survival, and objective response rates in patients with untreated advanced renal cell carcinoma compared to sunitinib, supporting its approval as a first-line therapy.

While the safety profile of the combination treatment is generally manageable, it requires careful monitoring and management of overlapping adverse events, such as diarrhea and hepatotoxicity, to maintain patient tolerability and treatment effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of adverse events associated with cabozantinib plus nivolumab in renal cell carcinoma: A review. McGregor, B., Mortazavi, A., Cordes, L., et al.[2023]

In a study of 59 patients with advanced nonsmall cell lung cancer, the combination of nimotuzumab with chemotherapy (docetaxel and carboplatin) significantly prolonged progression-free survival by 1 month compared to chemotherapy alone.

Nimotuzumab was well tolerated, with only mild skin rashes reported, indicating a favorable safety profile while potentially enhancing the effectiveness of treatment as shown by significant decreases in certain tumor markers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A clinical trial on docetaxel and carboplatin therapy with or without nimotuzumab for the treatment of advanced nonsmall cell lung cancer. Qi, D., Cui, Y., Wang, Q., et al.[2018]

Nivolumab, an immune checkpoint inhibitor, significantly improved overall survival and progression-free survival compared to docetaxel in patients with advanced squamous non-small cell lung cancer (NSCLC) in the CheckMate 017 trial.

Nivolumab was better tolerated than docetaxel, with manageable adverse effects, making it a promising treatment option for patients who have already undergone chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab: a review in advanced squamous non-small cell lung cancer. Keating, GM.[2022]

Cabozantinib (CAB) has shown significant improvements in overall survival and progression-free survival in phase-III studies for patients with advanced renal cell carcinoma and hepatocellular carcinoma, leading to its approval in Japan for these conditions.

CAB may enhance antitumor immunity and, when combined with PD-1 checkpoint inhibitors like nivolumab, has demonstrated increased progression-free survival compared to standard treatments, indicating a potential synergistic effect in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pharmacological properties and clinical outcomes of the anti-cancer drug, cabozantinib (CABOMETYX®)]. Osaka, T., Yamaguchi, N., Hara, T.[2022]

In a phase 3 trial involving 651 patients with untreated advanced renal-cell carcinoma, the combination of nivolumab and cabozantinib significantly improved progression-free survival (16.6 months) compared to sunitinib (8.3 months), with a hazard ratio of 0.51, indicating a 49% reduction in the risk of disease progression or death.

Patients receiving nivolumab plus cabozantinib also had a higher overall survival rate at 12 months (85.7%) compared to those on sunitinib (75.6%), and a greater objective response rate (55.7% vs. 27.1%), although adverse events were common in both groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nivolumab plus Cabozantinib versus Sunitinib for Advanced Renal-Cell Carcinoma. Choueiri, TK., Powles, T., Burotto, M., et al.[2022]

In a phase 3 trial involving 855 patients with untreated advanced renal-cell carcinoma, the combination of cabozantinib with nivolumab and ipilimumab significantly improved progression-free survival compared to nivolumab and ipilimumab alone, with a 12-month progression-free survival rate of 57% versus 49%.

However, the experimental group experienced a higher incidence of severe adverse events (grade 3 or 4) at 79%, compared to 56% in the control group, indicating a trade-off between efficacy and safety.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib plus Nivolumab and Ipilimumab in Renal-Cell Carcinoma. Choueiri, TK., Powles, T., Albiges, L., et al.[2023]

In a real-world analysis of adverse events from two combination therapies for advanced renal cell carcinoma, cabozantinib (CAB) plus nivolumab (NIVO) showed higher incidence rates of seven types of toxicities compared to ipilimumab (IPI) plus NIVO.

Conversely, IPI + NIVO was associated with higher rates of three types of toxicities and had a greater incidence of serious adverse events, suggesting that both therapies have distinct safety profiles that can guide treatment decisions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse Events of Cabozantinib Plus Nivolumab Versus Ipilimumab Plus Nivolumab. Blas, L., Shiota, M., Tsukahara, S., et al.[2023]

In a phase 2 trial involving 117 patients with advanced, refractory squamous non-small-cell lung cancer, nivolumab demonstrated a 14.5% objective response rate, indicating its potential effectiveness as a treatment option.

The safety profile of nivolumab was manageable, with 17% of patients experiencing severe treatment-related adverse events, suggesting that while there are risks, the benefits may outweigh them for patients with limited treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial. Rizvi, NA., Mazières, J., Planchard, D., et al.[2022]

Cabozantinib is an oral multitargeted tyrosine kinase inhibitor approved for advanced renal cell carcinoma and progressive metastatic medullary thyroid cancer, showing potential advantages over single-receptor TKIs.

The article reviews clinical trial data and management strategies for common adverse events associated with cabozantinib, highlighting its expanding use in treating various cancers such as prostate, hepatocellular, and lung cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cabozantinib: A Multitargeted Oral Tyrosine Kinase Inhibitor. Markowitz, JN., Fancher, KM.[2019]

Current treatments for non-small cell lung cancer (NSCLC) have a low 5-year survival rate of only 15%, highlighting the need for improved therapies targeting specific tumor pathways.

Nimotuzumab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), has shown clinical benefits in NSCLC and may be expanded for use in additional treatment settings due to its effectiveness against the upregulated EGFR found in 40%-80% of NSCLC cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The emerging role of nimotuzumab in the treatment of non-small cell lung cancer. Boland, W., Bebb, G.[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]

In a phase Ib/II study involving 64 patients with progressive non-small cell lung cancer (NSCLC) who had previously received erlotinib, cabozantinib alone showed a modest objective response rate (ORR) of 8.2%, indicating some efficacy as a treatment option.

However, in the phase II portion, the combination of cabozantinib and erlotinib did not yield any responses in patients with acquired resistance to erlotinib, suggesting that cabozantinib did not effectively re-sensitize these patients to erlotinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase Ib/II study of cabozantinib (XL184) with or without erlotinib in patients with non-small cell lung cancer. Wakelee, HA., Gettinger, S., Engelman, J., et al.[2023]

Citations

1. ir.exelixis.com ir.exelixis.com/news-releases/news-release-details/exelixis-announces-results-subgroup-analysis-cabinet-phase-3

Press Release - Exelixis CABOMETYX reduced the risk of disease progression or death by 81% versus placebo in patients with advanced lung or thymic neuroendocrine ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5143197/

A Phase 2 Single Arm Trial of Cabozantinib in Patients with ... Cabozantinib is a multikinase RET inhibitor that produced a 10% response rate in unselected patients with lung cancers.

3. ipsen.com ipsen.com/press-releases/asco-2022-new-cabometyx-data-show-encouraging-results-in-monotherapy-and-in-combination-across-different-tumor-types-including-metastatic-non-small-cell-lung-cancer/

ASCO 2022: New Cabometyx® data show encouraging ... These data show that the therapeutic potential of Cabometyx as a key treatment option in a broad range of tumors is continuing to be realized.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7023875/

Effective Treatment with Cabozantinib in an Advanced Non ... As to lung cancer, cabozantinib has been reported to have strong and selective anti-ROS1 activity, especially against solvent-front resistance ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S1558767323002173

Real-World Results of Cabozantinib Given as Alternative ... An alternative treatment schedule was offered in 39.1% of patients. Objective responses were found in 43.3% (CR 6%) of patients and the median PFS was 10.8 ...

6. cabometyxhcp.com cabometyxhcp.com/rcc-treatment/monotherapy/safety

CABOSUN & METEOR show similar safety results for ... Laboratory abnormalities occurring in ≥25% of patients in the CABOMETYX arm of the METEOR trial · Grade 3-4 adverse reactions (ARs) occurring in >1% of patients ...

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2012/203756lbl.pdf

COMETRIQ™ (cabozantinib) Label - accessdata.fda.gov The safety of COMETRIQ was evaluated in 330 patients with progressive metastatic medullary thyroid cancer randomized to receive 140 mg COMETRIQ (n = 214) or ...

8. cabometyx.com cabometyx.com/

CABOMETYX® (cabozantinib) Patient Website CABOMETYX is a prescription medicine used to treat people with certain types of neuroendocrine tumors and thyroid, liver, and advanced kidney cancers.

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5905684/

Management of Adverse Events Associated with ... This review reports on the safety profile of cabozantinib in patients with advanced renal cell carcinoma and offers guidance on the management of adverse ...

10. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2021/208692s010lbl.pdf

CABOMETYX (cabozantinib) - accessdata.fda.gov The safety of CABOMETYX was evaluated in METEOR, a randomized, open-label trial in which 331 patients with advanced renal cell carcinoma received CABOMETYX 60 ...