Alectinib + Cobimetinib for Lung Cancer

Overseen By Ibiayi Dagogo-Jack, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Massachusetts General Hospital

Must be taking: Alectinib

Must not be taking: CYP3A4 inhibitors, CYP3A4 inducers

Disqualifiers: Pregnancy, HIV, Heart failure, others

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

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

Compensation: Varies

Number of Visits: Unknown

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment for ALK+ non-small cell lung cancer. Researchers are examining whether a combination of two drugs, Alectinib (Alecensa) and Cobimetinib (Cotellic), can serve as an effective treatment option. The study seeks participants with this type of lung cancer who have experienced disease progression after taking Alectinib. Those dealing with ALK+ lung cancer and willing to follow the study's guidelines might be suitable candidates for this trial. As a Phase 1, Phase 2 trial, the research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group.

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

The trial protocol does not specify if you need to stop all current medications, but it does mention a washout period (time without taking certain medications) for tyrosine kinase inhibitors (TKIs) before starting the study treatment. If you are on crizotinib, a 7-day washout is required, but no washout is needed if you are currently on alectinib. Additionally, you cannot use certain drugs that affect the liver enzyme CYP3A4 during the trial.

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

Research has shown that the combination of alectinib and cobimetinib has been tested for safety in patients with ALK-positive lung cancer. In these studies, no serious side effects were found at the starting dose that would prevent increasing the dose. However, increasing the dose of cobimetinib led some patients to experience more significant side effects related to creatine levels in the blood.

Alectinib alone has been linked to side effects such as bradycardia, a slower than normal heart rate. One study found that about 42% of patients developed this condition, and a few required additional treatment. Despite this, alectinib is already approved for treating lung cancer, indicating it is considered safe for certain patients.

Overall, while some side effects have occurred, these treatments have been studied for safety, and the combination has not shown severe issues at lower doses. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Alectinib and Cobimetinib for lung cancer because these drugs target cancer cells in a novel way. Alectinib is an ALK inhibitor, which blocks a specific protein involved in the growth of cancer cells, while Cobimetinib inhibits MEK, a key enzyme in a different signaling pathway that helps cancer cells survive. This combination aims to tackle cancer from two angles, potentially making it more effective than current standard treatments, like chemotherapy, which often come with harsh side effects. By using targeted treatments, there's hope for improved outcomes with fewer side effects for patients with lung cancer.

What evidence suggests that this drug combination could be an effective treatment for ALK+ non-small cell lung cancer?

Research has shown mixed results when using alectinib with cobimetinib for treating ALK-positive non-small cell lung cancer. For patients who had not previously taken alectinib, this combination prevented cancer progression for about 49.2 months. However, for those whose cancer did not respond to alectinib alone, the combination proved less effective, with progression occurring after only 2.2 months. Notably, some side effects, such as skin problems and changes in muscle enzymes, were significant enough to require dose adjustments for some patients. Participants in this trial will receive the combination of alectinib and cobimetinib to further evaluate its effectiveness and safety. ^{2 3 4 6 7}

Who Is on the Research Team?

Ibiayi Dagogo-Jack, MD

Principal Investigator

Massachusetts General Hospital

Are You a Good Fit for This Trial?

This trial is for adults with advanced ALK-positive non-small cell lung cancer who have seen their disease progress on alectinib. They should be able to perform daily activities (ECOG ≤ 2), swallow pills, and have a life expectancy over 12 weeks. Pregnant women, those unable or unwilling to use contraception, and individuals with certain health conditions or treatments are excluded.

Inclusion Criteria

For all women of childbearing potential: Negative pregnancy test and agreement to remain abstinent or use two adequate methods of contraception

I have not had chemotherapy or only had platinum-based chemo for advanced cancer.

I am taking seizure medication that does not induce enzymes.

Exclusion Criteria

I have had a previous transplant of stem cells or an organ.

I have had symptoms of heart failure recently or currently.

I have pain from my cancer that isn't managed well.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase I Treatment

Participants receive alectinib and cobimetinib to determine safety and appropriate dosing

4 weeks

Weekly visits for dose escalation and monitoring

Phase II Treatment

Participants receive the safest doses of alectinib and cobimetinib to evaluate effectiveness

2 years

Monthly visits for treatment and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

2 years

Periodic visits for monitoring

What Are the Treatments Tested in This Trial?

Interventions

• Alectinib
• Cobimetinib

Trial Overview The study tests combining Alectinib with Cobimetinib as a treatment for ALK+ NSCLC. Participants must have previously experienced disease progression while on Alectinib alone and meet specific health criteria to join the study.

How Is the Trial Designed?

Group I: Cobimetinib + Alectinib Experimental Treatment 2 Interventions

Alectinib administered twice daily at pre-determined dosage orally Cobimetinib administered daily at pre-determined dosage orally

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

Approved in United States as Alecensa for:

• Metastatic ALK-positive non-small cell lung cancer (NSCLC)
• Adjuvant treatment following tumor resection in patients with ALK-positive NSCLC

Approved in European Union as Alecensa for:

• Metastatic ALK-positive non-small cell lung cancer (NSCLC)
• Adjuvant treatment following tumor resection in patients with ALK-positive NSCLC

Who Is Running the Clinical Trial?

Massachusetts General Hospital

Lead Sponsor

Trials

3,066

Recruited

13,430,000+

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Published Research Related to This Trial

In a trial involving 385 patients with advanced non-small cell lung cancer (NSCLC), the combination of ganetespib and docetaxel showed an acceptable safety profile, with neutropenia being the most common severe side effect, affecting 41% of patients in the combination group.

Although the primary endpoints for progression-free survival (PFS) were not met in the overall population, significant benefits were observed in patients diagnosed with advanced adenocarcinoma more than 6 months prior, indicating potential for this subgroup to benefit from the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A randomized phase II study of ganetespib, a heat shock protein 90 inhibitor, in combination with docetaxel in second-line therapy of advanced non-small cell lung cancer (GALAXY-1). Ramalingam, S., Goss, G., Rosell, R., et al.[2020]

Alectinib significantly improves overall survival compared to crizotinib in patients with metastatic or locally advanced ALK-positive non-small cell lung cancer (NSCLC), based on a systematic review of 13 randomized controlled trials.

In terms of progression-free survival, alectinib also outperformed crizotinib and ceritinib, demonstrating a favorable safety profile compared to other ALK inhibitors, particularly in patients with brain metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alectinib for treating patients with metastatic ALK-positive NSCLC: systematic review and network metanalysis. Samacá-Samacá, D., Prieto-Pinto, L., Peréz, AY., et al.[2023]

In a phase II trial involving 88 chemotherapy-naive patients with advanced adenocarcinoma with bronchioloalveolar carcinoma subtype (ADC-BAC), gefitinib achieved a disease control rate of 29.4%, indicating its efficacy as a first-line treatment.

Gefitinib was associated with low toxicity, with common side effects including dermatological issues, diarrhea, and nausea, making it a suitable option for patients, especially those with the nonmucinous subtype of ADC-BAC, who showed better progression-free and overall survival rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

IFCT-0401 Trial: a phase II study of gefitinib administered as first-line treatment in advanced adenocarcinoma with bronchioloalveolar carcinoma subtype. Cadranel, J., Quoix, E., Baudrin, L., et al.[2018]

Alectinib is a second-generation, orally active drug specifically designed to target ALK-positive non-small cell lung cancer (NSCLC) in patients who have developed resistance to the first-line treatment, crizotinib.

The FDA has granted Alectinib several designations, including orphan drug and breakthrough therapy status, highlighting its potential as a significant treatment option for patients with advanced NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Personalized Medicine Tackles Clinical Resistance: Alectinib in ALK-Positive Non-Small Cell Lung Cancer Progressing on First-Generation ALK Inhibitor. Skoulidis, F., Papadimitrakopoulou, VA.[2019]

In a study involving 623 patients with advanced non-small-cell lung cancer, the addition of bexarotene to standard chemotherapy (cisplatin/vinorelbine) did not significantly improve overall survival compared to chemotherapy alone.

However, a subgroup of patients treated with bexarotene who developed high-grade hypertriglyceridemia showed a potential survival benefit, suggesting that triglyceride response could serve as a biomarker for treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized phase III trial comparing bexarotene (L1069-49)/cisplatin/vinorelbine with cisplatin/vinorelbine in chemotherapy-naive patients with advanced or metastatic non-small-cell lung cancer: SPIRIT I. Ramlau, R., Zatloukal, P., Jassem, J., et al.[2022]

Alectinib has been shown to significantly improve progression-free survival and overall survival compared to crizotinib in patients with advanced ALK-positive non-small-cell lung cancer, as demonstrated in the phase III ALEX study and confirmed in subsequent studies in Japanese and Asian populations.

The safety profile of alectinib is manageable, with most adverse events being treatable through dose reduction, and no new safety concerns have emerged during long-term follow-up, reinforcing its recommendation as a preferred first-line therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical experience and management of adverse events in patients with advanced ALK-positive non-small-cell lung cancer receiving alectinib. Dziadziuszko, R., Peters, S., Ruf, T., et al.[2023]

Alectinib shows a high overall response rate of 70% and a disease control rate of 88% in treating non-small cell lung cancer, based on a meta-analysis of 8 studies involving 626 patients.

While alectinib is generally well-tolerated, it has a higher incidence of certain side effects like myalgia (18%) and anemia (25%) compared to the first-generation ALK inhibitor crizotinib, indicating the need for monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and safety of alectinib in the treatment of ALK+ NSCLC: a systematic review and meta-analysis. Fan, J., Xia, Z., Zhang, X., et al.[2022]

Alectinib is an effective next-generation ALK inhibitor for patients with metastatic ALK-positive non-small-cell lung cancer (NSCLC), showing improved progression-free survival and a reduction in brain metastases compared to crizotinib, especially in patients who are intolerant or have progressed on crizotinib.

Common side effects of alectinib include fatigue, constipation, and peripheral edema, with more serious effects being increases in liver enzymes and creatine phosphokinase, indicating it is generally well-tolerated in clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alectinib for advanced ALK-positive non-small-cell lung cancer. Ly, AC., Olin, JL., Smith, MB.[2019]

Alectinib, while effective for treating advanced non-small-cell lung cancer (NSCLC) with ALK rearrangements, can lead to serious side effects such as grade 4 hyperbilirubinemia, as seen in a patient after five months of treatment.

After discontinuing alectinib and using an artificial liver support system to manage the hyperbilirubinemia, the patient was successfully treated with ensartinib, achieving stable disease without recurrence of hyperbilirubinemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful Treatment with Ensartinib After Alectinib-induced Hyperbilirubinemia in ALK-Positive NSCLC. Peng, L., Xiao, K., Cui, J., et al.[2022]

In a phase III trial involving 107 patients with advanced ALK-positive non-small-cell lung cancer, alectinib demonstrated a significantly longer median progression-free survival (PFS) of 9.6 months compared to just 1.4 months for standard chemotherapy, indicating its superior efficacy.

Alectinib also showed a higher objective response rate in patients with central nervous system disease (54.2% vs. 0% for chemotherapy) and had a more favorable safety profile, with fewer grade ≥3 adverse events (27.1% for alectinib vs. 41.2% for chemotherapy).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alectinib versus chemotherapy in crizotinib-pretreated anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer: results from the phase III ALUR study. Novello, S., Mazières, J., Oh, IJ., et al.[2022]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39615410/

Alectinib combined with cobimetinib in ALK-Rearranged lung ... Alectinib combined with cobimetinib demonstrated limited activity in alectinib-resistant tumors. Despite dose-limiting dermatologic and muscle enzyme ...

2. lungcancerjournal.info lungcancerjournal.info/article/S0169-5002(24)00537-3/fulltext

Alectinib combined with cobimetinib in ALK-Rearranged lung ... Median progression-free survival was 2.2 and 49.2 months for alectinib-resistant and alectinib-naïve tumors, respectively. Abstract.

3. clinicaltrials.gov clinicaltrials.gov/study/NCT03202940

NCT03202940 | A Phase IB/II Study of Alectinib Combined ... Alectinib has been tested in other clinical research studies and results show that the drug may help stop the growth and spread of ALK+ lung cancer cells. ...

4. jacc.org jacc.org/doi/10.1016/j.jaccao.2022.09.006

Cardiac Toxicity of Alectinib in Patients With ALK+ Lung ... Twenty-two patients (42%) developed alectinib-related bradycardia (6 symptomatic bradycardia). One patient underwent a pacemaker implantation for severe ...

5. sciencedirect.com sciencedirect.com/science/article/pii/S0147027224000060

Targeting MEK in non-small cell lung cancer The overall conclusions from these trials were that MEK inhibitor monotherapy possessed minimal clinical efficacy and may even be more toxic than traditional ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC12096152/

Alectinib Combined with Cobimetinib in ALK-Rearranged ... All 16 patients were evaluable for safety (Table 2). No DLTs were observed at the entry dose level (alectinib 600 mg twice daily continuously + ...

7. clinicaltrials.gov clinicaltrials.gov/study/NCT03178552

NCT03178552 | A Study to Evaluate the Efficacy and ... A Study to Evaluate the Efficacy and Safety of Multiple Targeted Therapies as Treatments for Participants With Non-Small Cell Lung Cancer (NSCLC) (B-FAST).