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

16 Participants Needed

Trial Summary

What is the purpose of this trial?

This research study is studying a drug combination as a possible treatment for anaplastic lymphoma kinase-positive (ALK+) non-small cell lung cancer. The drugs involved in this study are: * Alectinib * Cobimetinib

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.

What data supports the effectiveness of the drug Alectinib in treating lung cancer?

Alectinib is a second-generation drug that is highly effective for treating advanced non-small cell lung cancer (NSCLC) with specific genetic changes (ALK-positive). It is approved for patients whose cancer has worsened after other treatments, showing its effectiveness in managing this type of lung cancer. ^{1 2 3 4 5}

What safety data exists for Alectinib and Cobimetinib in humans?

Alectinib has been shown to have a manageable safety profile in patients with advanced ALK-positive non-small-cell lung cancer, with most side effects being manageable by adjusting the dose. However, it can cause serious side effects, and some effects like muscle pain and swelling are not fully understood. ^{6 7 8 9 10}

How is the drug combination of Alectinib and Cobimetinib unique for lung cancer treatment?

The combination of Alectinib and Cobimetinib is unique because it targets specific proteins involved in cancer cell growth, potentially offering a new approach for treating lung cancer compared to traditional chemotherapy. Alectinib is known for targeting ALK (anaplastic lymphoma kinase) mutations, while Cobimetinib inhibits MEK (a protein involved in cell signaling), which may provide a more tailored treatment option for certain patients. ^{11 12 13 14 15}

Research Team

Ibiayi Dagogo-Jack, MD

Principal Investigator

Massachusetts General Hospital

Eligibility Criteria

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

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

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

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

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

Treatment Details

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.

Participant Groups

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

Findings from Research

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]

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 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 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]

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 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]

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]

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]

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]

References

1. United States 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. [2019]

2. Greece pubmed.ncbi.nlm.nih.gov

Efficacy of Ceritinib After Alectinib for ALK-positive Non-small Cell Lung Cancer. [2020]

3. Korea (South) pubmed.ncbi.nlm.nih.gov

First-Line Alectinib vs. Brigatinib in Advanced NSCLC with ALK Rearrangement: Real-World Data. [2023]

4. New Zealand pubmed.ncbi.nlm.nih.gov

The efficacy and safety of alectinib in the treatment of ALK+ NSCLC: a systematic review and meta-analysis. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Safety and activity of alectinib plus bevacizumab in patients with advanced ALK-rearranged non-small-cell lung cancer: a phase I/II study. [2022]

6. England 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. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Alectinib for advanced ALK-positive non-small-cell lung cancer. [2019]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Successful Treatment with Ensartinib After Alectinib-induced Hyperbilirubinemia in ALK-Positive NSCLC. [2022]

9. England pubmed.ncbi.nlm.nih.gov

Alectinib for treating patients with metastatic ALK-positive NSCLC: systematic review and network metanalysis. [2023]

10. England 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. [2022]

11. England 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). [2020]

12. Ireland pubmed.ncbi.nlm.nih.gov

Outcomes of patients with advanced non-small cell lung cancer treated with gefitinib (ZD1839, "Iressa") on an expanded access study. [2018]

13. United States pubmed.ncbi.nlm.nih.gov

Multi-Institutional Randomized Phase II Trial of Gefitinib for Previously Treated Patients With Advanced Non-Small-Cell Lung Cancer. [2023]

14. United States 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. [2018]

15. United States 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. [2022]