Combination Therapy for Non-Small Cell Lung Cancer

Overseen By Yasir Elamin, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Strong CYP3A inhibitors, Strong CYP3A inducers

Disqualifiers: Leptomeningeal disease, Recent malignancy, 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: 5

12 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires stopping the use of certain medications, such as strong CYP3A inhibitors, strong CYP3A inducers, and CYP3A substrates with a narrow therapeutic window. Additionally, any anticancer herbal medications should be stopped before joining the study.

What data supports the effectiveness of the drug combination therapy for non-small cell lung cancer?

Research shows that the combination of pemetrexed, carboplatin, and bevacizumab is effective in treating advanced non-small cell lung cancer, as it has been compared favorably to other drug combinations in terms of response and survival outcomes. ^{1 2 3 4 5}

Is the combination therapy for non-small cell lung cancer safe?

The combination of pemetrexed, carboplatin, and bevacizumab has been studied for safety in patients with non-small cell lung cancer. While generally considered safe, pemetrexed can cause kidney issues, especially in patients with pre-existing kidney problems. Bevacizumab has shown efficacy and safety in advanced lung cancer, but like all treatments, it may have side effects. ^{1 2 3 6 7}

What makes the combination therapy of Bevacizumab, Carboplatin, Ensartinib, and Pemetrexed unique for treating non-small cell lung cancer?

This combination therapy is unique because it includes Ensartinib, a newer drug that targets specific cancer cell growth signals, alongside Bevacizumab, Carboplatin, and Pemetrexed, which are already known to be effective in treating non-squamous non-small cell lung cancer. This approach aims to enhance treatment efficacy by combining different mechanisms of action. ^{2 3 4 8 9}

What is the purpose of this trial?

This phase Ib trial finds the best dose and side effects of ensartinib and its effects when given with carboplatin, pemetrexed and bevacizumab for in treating patients with ALK-positive non-small cell lung cancer that is stage IIIC or IV, or has come back (recurrent). Ensartinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Chemotherapy drugs, such as carboplatin and pemetrexed, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Bevacizumab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread. Giving ensartinib, carboplatin, pemetrexed and bevacizumab may help to control the disease.

Research Team

Yasir Y. Elamin

Principal Investigator

M.D. Anderson Cancer Center

Eligibility Criteria

Adults with ALK-positive non-small cell lung cancer at stage IIIC, IV, or recurrent who can swallow pills and have a life expectancy of over 12 weeks. They may be treatment-naive or have had prior treatments but must meet specific blood count and organ function criteria. Pregnant women, those with recent serious heart issues, other cancers within 2 years (except certain skin/cervical cancers), active infections, or severe medical conditions are excluded.

Inclusion Criteria

I can swallow and keep down pills.

My blood clotting time is normal or managed if I'm on blood thinners.

You are expected to live for at least 12 more weeks.

Exclusion Criteria

You are allergic to the dye used in the ensartinib 100 mg capsule.

I haven't had cancer in the last 2 years, except for certain skin cancers, cervical cancers, or any cured cancer.

I haven't had serious heart or stroke issues in the last 6 months.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Therapy

Patients receive ensartinib, carboplatin, pemetrexed, and bevacizumab. Treatment repeats every 21 days for up to 4 cycles.

12 weeks

4 visits (in-person)

Maintenance Therapy

Patients receive ensartinib and bevacizumab. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Variable, based on disease progression

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

1 visit (in-person)

Treatment Details

Interventions

• Bevacizumab
• Carboplatin
• Ensartinib
• Pemetrexed

Trial Overview The trial is testing the combination of Ensartinib (a growth-blocking enzyme inhibitor) with Carboplatin and Pemetrexed (chemotherapy drugs), plus Bevacizumab (a monoclonal antibody that hinders tumor spread). The goal is to find the optimal dose of Ensartinib and assess its effectiveness alongside these drugs in controlling advanced lung cancer.

Participant Groups

Group I: Treatment (ensartinib, carboplatin, pemetrexed, bevacizumab) Experimental Treatment 4 Interventions

INDUCTION THERAPY: Patients receive ensartinib PO QD on days 1-21, carboplatin IV over 15-60 minutes on day 1, pemetrexed IV over 10 minutes on day 1 and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE THERAPY: Patients receive ensartinib PO QD on days 1-21 and bevacizumab IV over 30-90 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Bevacizumab is already approved in European Union, United States, Japan, Canada for the following indications:

Approved in European Union as Avastin for:

• Colorectal cancer
• Breast cancer
• Non-small cell lung cancer
• Renal cell carcinoma
• Ovarian cancer

Approved in United States as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Glioblastoma
• Renal cell carcinoma
• Cervical cancer
• Ovarian cancer

Approved in Japan as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Breast cancer
• Renal cell carcinoma
• Ovarian cancer

Approved in Canada as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Breast cancer
• Renal cell carcinoma
• Ovarian cancer

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Findings from Research

In a study involving 939 patients with advanced nonsquamous non-small-cell lung cancer, the combination of pemetrexed, carboplatin, and bevacizumab (PemCBev) did not show a significant improvement in overall survival compared to paclitaxel, carboplatin, and bevacizumab (PacCBev), with median overall survival times of 12.6 and 13.4 months, respectively.

However, PemCBev demonstrated a significantly better progression-free survival (6.0 months vs. 5.6 months) and had a different toxicity profile, with more cases of anemia and thrombocytopenia, while PacCBev was associated with higher rates of neutropenia and alopecia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. Patel, JD., Socinski, MA., Garon, EB., et al.[2022]

In a study involving 361 patients with advanced nonsquamous non-small-cell lung cancer, the combination of pemetrexed and carboplatin (Pem+Cb) did not show a significant advantage in progression-free survival without grade 4 toxicity compared to paclitaxel, carboplatin, and bevacizumab (Pac+Cb+Bev).

While both treatment regimens were generally well tolerated, Pem+Cb was associated with higher rates of grade 3/4 anemia and thrombocytopenia, whereas Pac+Cb+Bev had more cases of grade 3/4 neutropenia and alopecia, indicating differing toxicity profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PRONOUNCE: randomized, open-label, phase III study of first-line pemetrexed + carboplatin followed by maintenance pemetrexed versus paclitaxel + carboplatin + bevacizumab followed by maintenance bevacizumab in patients ith advanced nonsquamous non-small-cell lung cancer. Zinner, RG., Obasaju, CK., Spigel, DR., et al.[2022]

In a study of 25 patients with stage IIIa lung adenocarcinoma, the combination of bevacizumab with pemetrexed and carboplatin as neoadjuvant chemotherapy showed a safety profile with manageable adverse events, including some cases of fatigue, neutropenia, and hypertension.

No severe perioperative complications such as hemorrhage or thromboembolic events were observed, suggesting that the neoadjuvant treatment is well-tolerated and safe for patients undergoing surgery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Safety of Neoadjuvant Bevacizumab plus Pemetrexed and Carboplatin in Patients with IIIa Lung Adenocarcinoma]. Zhang, S., Xu, P., Yuan, C., et al.[2019]

In a study of 108 patients with advanced non-squamous non-small cell lung cancer (NSCLC), adding bevacizumab to pemetrexed as maintenance therapy significantly improved progression-free survival (PFS) compared to pemetrexed alone, with PFS of 7.0 months versus 5.4 months.

Patients who responded partially to initial treatment had a median overall survival of 29.6 months with the addition of bevacizumab, compared to 23.3 months with pemetrexed alone, suggesting a potential survival benefit from the combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized, Phase II study of pemetrexed plus bevacizumab versus pemetrexed alone after treatment with cisplatin, pemetrexed, and bevacizumab in advanced non-squamous, non-small cell lung cancer: TORG (thoracic oncology research group) 1321. Kasai, T., Mori, K., Nakamura, Y., et al.[2023]

Pemetrexed is an effective treatment for relapsed or chemotherapy-refractory non-small cell lung cancer (NSCLC), showing similar response and survival rates to taxotere but with less toxicity.

When combined with platinum analogs or other chemotherapy agents like gemcitabine or vinorelbine, pemetrexed produces equivalent responses and overall survival outcomes, suggesting it is a viable option in NSCLC treatment regimens.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Role of pemetrexed in non-small cell lung cancer. Longo-Sorbello, GS., Chen, B., Budak-Alpdogan, T., et al.[2022]

The combination of pemetrexed, platinum, and pembrolizumab shows manageable toxicity, with most severe adverse events occurring early in treatment and resolving within two weeks, indicating a favorable safety profile for long-term use.

While there was a slightly higher incidence of renal toxicity in patients receiving the pembrolizumab combination compared to those on pemetrexed alone, this did not increase with longer treatment durations, supporting the regimen's safety in clinical practice.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety of pemetrexed plus platinum in combination with pembrolizumab for metastatic nonsquamous non-small cell lung cancer: A post hoc analysis of KEYNOTE-189. Garon, EB., Aerts, J., Kim, JS., et al.[2023]

In a study of 29 non-small-cell lung cancer patients treated with pemetrexed, 21% developed acute kidney injury (AKI) despite having an initial eGFR above the recommended threshold of 45 mL/min, indicating potential renal toxicity even in patients considered safe for treatment.

Patients with a baseline eGFR below 60 mL/min were more likely to experience AKI, suggesting that careful monitoring and management of renal function and risk factors are essential when administering pemetrexed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemetrexed induced acute kidney injury in patients with non-small cell lung cancer: reversible and chronic renal damage. Rombolà, G., Vaira, F., Trezzi, M., et al.[2021]

In a study of 1,534 patients with advanced non-squamous non-small cell lung cancer, the combination of platinum/paclitaxel/bevacizumab resulted in a significantly higher overall response rate (ORR) of 40.8% compared to 32.7% for platinum/pemetrexed.

Despite the better ORR with the paclitaxel/bevacizumab regimen, there was no significant difference in progression-free survival (PFS) or overall survival (OS) between the two treatment groups, suggesting that both regimens are similarly effective and should be chosen based on side effect profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of Chemotherapeutic Regimens Frequently Used in Metastatic Non-squamous NSCLC Treatment. Krejci, D., Opalka, P., Krejci, J., et al.[2021]

In a study of 72 patients with advanced non-small cell lung cancer, the combination of bevacizumab and pemetrexed resulted in a significantly longer overall survival time of 14 months compared to 11 months for those receiving only pemetrexed.

While the combination therapy showed improved overall response and disease control rates, these differences were not statistically significant, indicating that while the combination may enhance survival, it does not drastically change response rates compared to pemetrexed alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical efficacy of bevacizumab concomitant with pemetrexed in patients with advanced non-small cell lung cancer. Zhang, YM., Li, YQ., Liu, ZH., et al.[2022]

References

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

PointBreak: a randomized phase III study of pemetrexed plus carboplatin and bevacizumab followed by maintenance pemetrexed and bevacizumab versus paclitaxel plus carboplatin and bevacizumab followed by maintenance bevacizumab in patients with stage IIIB or IV nonsquamous non-small-cell lung cancer. [2022]

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

PRONOUNCE: randomized, open-label, phase III study of first-line pemetrexed + carboplatin followed by maintenance pemetrexed versus paclitaxel + carboplatin + bevacizumab followed by maintenance bevacizumab in patients ith advanced nonsquamous non-small-cell lung cancer. [2022]

3. China pubmed.ncbi.nlm.nih.gov

[Safety of Neoadjuvant Bevacizumab plus Pemetrexed and Carboplatin in Patients with IIIa Lung Adenocarcinoma]. [2019]

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

Randomized, Phase II study of pemetrexed plus bevacizumab versus pemetrexed alone after treatment with cisplatin, pemetrexed, and bevacizumab in advanced non-squamous, non-small cell lung cancer: TORG (thoracic oncology research group) 1321. [2023]

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

Role of pemetrexed in non-small cell lung cancer. [2022]

6. Ireland pubmed.ncbi.nlm.nih.gov

Safety of pemetrexed plus platinum in combination with pembrolizumab for metastatic nonsquamous non-small cell lung cancer: A post hoc analysis of KEYNOTE-189. [2023]

7. Italy pubmed.ncbi.nlm.nih.gov

Pemetrexed induced acute kidney injury in patients with non-small cell lung cancer: reversible and chronic renal damage. [2021]

8. Greece pubmed.ncbi.nlm.nih.gov

Comparison of Chemotherapeutic Regimens Frequently Used in Metastatic Non-squamous NSCLC Treatment. [2021]

9. Thailand pubmed.ncbi.nlm.nih.gov

Clinical efficacy of bevacizumab concomitant with pemetrexed in patients with advanced non-small cell lung cancer. [2022]