Chemotherapy + Bevacizumab +/- Immunotherapy for Advanced Non-Small Cell Lung Cancer

Overseen By Joseph Bodor, MD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Fox Chase Cancer Center

Must be taking: TKIs

Must not be taking: Immunomodulatory agents, Chemotherapy

Disqualifiers: Cirrhosis, Hypertension, Autoimmune disease, 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: Unknown

Duration: 12.5 months

117 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests new treatment combinations for advanced non-small cell lung cancer (NSCLC) in individuals who have smoked fewer than 100 cigarettes in their lifetime or have specific genetic mutations. Researchers aim to determine if adding the immunotherapy drug atezolizumab (Tecentriq) to standard chemotherapy and bevacizumab (a drug that inhibits blood vessel growth in tumors) can improve outcomes. Participants must have NSCLC with certain genetic markers or be never smokers with no prior chemotherapy or immunotherapy treatments. This study seeks to identify better treatment options for this specific group of lung cancer patients. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to potentially groundbreaking advancements in lung cancer therapy.

Will I have to stop taking my current medications?

The trial requires a minimum washout period (time without taking certain medications) of 3 days for patients with EGFR mutations who have been on TKIs (targeted cancer therapies). Other medications are not specifically mentioned, so it's best to discuss your current medications with the trial team.

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

Research has shown that the combination of atezolizumab, bevacizumab, carboplatin, and pemetrexed is generally well-tolerated by patients with non-small cell lung cancer (NSCLC). In past studies, patients who received similar drug combinations reported manageable side effects and found the treatment tolerable.

For instance, one study comparing atezolizumab with other drugs found that patients lived longer and experienced survival benefits. While side effects such as tiredness, nausea, and low blood counts occurred, they were usually mild to moderate.

The safety profile of this drug combination appears promising, suggesting it could be a viable option for those considering joining the trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for advanced non-small cell lung cancer because they combine chemotherapy with bevacizumab, and potentially with immunotherapy, to enhance effectiveness. Unlike standard treatments, which often rely solely on chemotherapy like carboplatin and pemetrexed, Arm A introduces atezolizumab, an immunotherapy that helps the immune system target cancer cells more effectively. Bevacizumab, present in both arms, inhibits blood vessel growth in tumors, potentially improving drug delivery to the cancer site. This approach offers a promising new way to tackle cancer by using the body's own defense mechanisms alongside traditional chemotherapy.

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

Research has shown that adding bevacizumab to chemotherapy can extend the lives of people with non-small cell lung cancer (NSCLC). Specifically, combining bevacizumab with the chemotherapy drugs carboplatin and paclitaxel resulted in patients living an average of 12.3 months, compared to 10.3 months with chemotherapy alone. In this trial, participants in Arm B will receive a combination of carboplatin, pemetrexed, and bevacizumab, followed by maintenance with pemetrexed and bevacizumab.

Immunotherapy, such as atezolizumab, has also proven effective for some patients with advanced NSCLC, extending their lives beyond what standard treatments offer. Participants in Arm A of this trial will receive atezolizumab in addition to carboplatin, pemetrexed, and bevacizumab, followed by maintenance with pemetrexed, bevacizumab, and atezolizumab. When used with other drugs like bevacizumab and chemotherapy, atezolizumab has significantly improved the time patients live without cancer progression. These findings suggest that this combination treatment could effectively manage advanced NSCLC. ^{2 5 6 7 8}

Who Is on the Research Team?

Joseph Bodor, MD

Principal Investigator

Fox Chase Cancer Center

Are You a Good Fit for This Trial?

Adults over 18 with stage IV non-squamous NSCLC who haven't had chemo, anti-VEGF, or immunotherapy (except certain TKIs for EGFR mutations). Must have measurable disease, adequate organ function, and no serious health issues like uncontrolled hypertension or recent bleeding. Smokers must have specific EGFR mutations; never-smokers can join without these mutations.

Inclusion Criteria

I am fully active or can carry out light work.

I completed my curative therapy over a year ago.

I am willing to use birth control if I can have children.

Exclusion Criteria

I have had a severe hypertension crisis or brain issues due to high blood pressure.

I do not have any uncontrolled illnesses or infections that would affect my participation.

I am willing to switch from denosumab to a bisphosphonate for the study.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Carboplatin + Pemetrexed + Bevacizumab, with or without Atezolizumab

12.5 months

Maintenance

Participants continue with Pemetrexed + Bevacizumab, with or without Atezolizumab

15 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Atezolizumab
• Bevacizumab
• Carboplatin
• Pemetrexed

Trial Overview

This trial tests if adding Atezolizumab to Carboplatin+Pemetrexed+Bevacizumab improves outcomes in advanced lung cancer. Participants are randomly assigned to receive either the four-drug combo (Arm B) or just the three drugs without Atezolizumab (Arm A).

How Is the Trial Designed?

Group I: Arm A Experimental Treatment 1 Intervention

Arm A: Carboplatin + Pemetrexed + Bevacizumab + Atezolizumab Maintenance: Pemetrexed + Bevacizumab + Atezolizumab

Group II: Arm B Active Control 1 Intervention

Arm B: Carboplatin + Pemetrexed + Bevacizumab Maintenance: Pemetrexed + Bevacizumab

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

Approved in United States as Tecentriq for:

• Melanoma
• Hepatocellular carcinoma
• Small cell lung cancer
• Non-small cell lung cancer
• Urothelial carcinoma

Approved in European Union as Tecentriq for:

• Melanoma
• Hepatocellular carcinoma
• Small cell lung cancer
• Non-small cell lung cancer
• Urothelial carcinoma

Who Is Running the Clinical Trial?

Fox Chase Cancer Center

Lead Sponsor

Trials

236

Recruited

39,300+

National Comprehensive Cancer Network

Collaborator

Trials

121

Recruited

7,400+

Published Research Related to This Trial

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 phase III trial involving 1,043 patients with advanced nonsquamous non-small-cell lung cancer, the combination of bevacizumab with cisplatin and gemcitabine significantly improved progression-free survival (PFS) compared to placebo, with hazard ratios of 0.75 for low-dose and 0.82 for high-dose bevacizumab.

The treatment also resulted in higher objective response rates (34.1% for low-dose and 30.4% for high-dose bevacizumab) compared to placebo (20.1%), while maintaining a similar incidence of serious adverse events across all treatment groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAil. Reck, M., von Pawel, J., Zatloukal, P., et al.[2022]

In a study of 102 patients with advanced non-squamous non-small cell lung cancer, both pembrolizumab and bevacizumab combined with pemetrexed-platinum chemotherapy showed comparable efficacy in terms of progression-free survival (PFS) and overall survival (OS).

Patients with a baseline neutrophil-to-lymphocyte ratio (NLR) of 3.10 or lower experienced significantly better overall survival when treated with bevacizumab, suggesting that this biomarker could help tailor treatment choices.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Direct Comparison Between the Addition of Pembrolizumab or Bevacizumab for Chemotherapy-Based First-Line Treatment of Advanced Non-Squamous Non-Small Cell Lung Cancer Lacking Driver Mutations. Liao, J., Liu, C., Long, Q., et al.[2022]

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]

In a real-life study of 121 patients with advanced non-squamous non-small cell lung cancer, the combination of pembrolizumab and chemotherapy resulted in a median progression-free survival of 9 months and overall survival of 20.6 months, demonstrating its efficacy as a first-line treatment.

The treatment was generally well-tolerated, with manageable side effects; however, 17.5% of patients experienced grade 3-4 adverse events, and there were two treatment-related deaths, indicating the need for careful monitoring during therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab plus pemetrexed-carboplatin combination in first-line treatment of advanced non-squamous non-small cell lung cancer: a multicenter real-life study (CAP29). Renaud, E., Ricordel, C., Corre, R., et al.[2023]

The combination of carboplatin, pemetrexed, and bevacizumab showed a response rate of 52% in 27 patients with advanced nonsquamous non-small-cell lung cancer (NSCLC), indicating its efficacy in treating this condition.

The treatment was generally well-tolerated, with no severe grade 4 or 5 toxicities reported, although some patients experienced manageable side effects like anemia and fatigue.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carboplatin/pemetrexed/bevacizumab in the treatment of patients with advanced non-small-cell lung cancer: a single-institution experience. Malhotra, B., Evans, T., Weiss, J., et al.[2022]

In a study of 57 patients with advanced non-small cell lung cancer (NSCLC), gefitinib and erlotinib showed significantly better progression-free survival (PFS) and overall survival (OS) compared to pemetrexed, with median PFS of 3.5 and 4.4 months versus 1.7 months for pemetrexed.

Both gefitinib and erlotinib had comparable efficacy and manageable safety profiles, indicating they may be more effective treatment options for certain patient subgroups, particularly those with non-squamous histology, males, and a smoking history.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pemetrexed versus gefitinib versus erlotinib in previously treated patients with non-small cell lung cancer. Hong, J., Kyung, SY., Lee, SP., et al.[2021]

In a study involving 1187 patients with nonsquamous non-small-cell lung cancer, the combination of atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP) showed a tolerable safety profile compared to other treatment regimens, with manageable adverse events during both induction and maintenance phases.

Patient-reported outcomes indicated that all treatment regimens, including ABCP, did not lead to significant declines in quality of life or physical functioning, suggesting that the addition of atezolizumab does not substantially increase the treatment burden for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and Patient-Reported Outcomes of Atezolizumab Plus Chemotherapy With or Without Bevacizumab Versus Bevacizumab Plus Chemotherapy in Non-Small-Cell Lung Cancer. Reck, M., Wehler, T., Orlandi, F., et al.[2021]

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]

Pemetrexed therapy showed a modest overall response rate of 15.8% in 59 chemotherapy-naïve patients with non-small-cell lung cancer (NSCLC), with a median survival of 7.2 months, indicating its potential efficacy as a treatment option.

The treatment was generally safe, with manageable toxicities such as myelosuppression and rash; however, it is recommended for patients with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 to minimize risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of pemetrexed disodium (ALIMTA, LY231514) in chemotherapy-naïve patients with advanced non-small-cell lung cancer. Clarke, SJ., Abratt, R., Goedhals, L., et al.[2022]

Bevacizumab combined with cisplatin and gemcitabine (BCG) shows a favorable hazard ratio for progression-free survival compared to pemetrexed and cisplatin (PC) in patients with advanced non-squamous non-small cell lung cancer (NSCLC).

BCG is more cost-effective than PC, with a lower monthly cost of 4,007 euros per patient and an incremental cost-effectiveness ratio of 34,919 euros per additional life-year gained, making it a viable first-line treatment option in Italy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost-effectiveness analysis of bevacizumab versus pemetrexed for advanced non-squamous NSCLC in Italy. Giuliani, G., Grossi, F., de Marinis, F., et al.[2022]

In a phase 2 study involving 199 treatment-naïve patients with advanced non-squamous non-small-cell lung cancer, the combination of cisplatin, pemetrexed, and bevacizumab (CisPemBev) showed a statistically significant improvement in progression-free survival (PFS) compared to carboplatin, paclitaxel, and bevacizumab (CarPacBev), with a median PFS of 7.6 months versus 7.0 months.

Both treatment regimens were well tolerated, but CisPemBev had a lower incidence of grade ≥3 adverse events (67%) compared to CarPacBev (82%), suggesting it may be a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bevacizumab plus platinum-based chemotherapy in advanced non-squamous non-small-cell lung cancer: a randomized, open-label phase 2 study (CLEAR). Udagawa, H., Sugiyama, E., Harada, T., et al.[2022]

In a study comparing pembrolizumab combined with chemotherapy to atezolizumab combined with chemotherapy (with or without bevacizumab) in patients with advanced non-squamous NSCLC, pembrolizumab showed significantly better overall survival (OS) and progression-free survival (PFS).

The analysis indicated that pembrolizumab + chemotherapy had a hazard ratio of 0.80 for OS and 0.79 for PFS compared to atezolizumab + chemotherapy, suggesting it may be a more effective treatment option for these patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab+chemotherapy versus atezolizumab+chemotherapy+/-bevacizumab for the first-line treatment of non-squamous NSCLC: A matching-adjusted indirect comparison. Halmos, B., Burke, T., Kalyvas, C., et al.[2021]

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