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

Recruiting in Palo Alto (17 mi)

Overseen by Joseph Treat, MD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

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

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

While cigarette smoking remains the primary cause of most lung cancer cases, lung carcinoma in never smokers account for nearly 20 percent of cases. Never smokers with lung cancer typically present with different molecular profiles from that of smokers, which results in prognostic and therapeutic implications. Molecular changes in NSCLC that have therapeutic significance include mutations in the epidermal growth factor receptor (EGFR) and rearrangements in the anaplastic lymphoma kinase (ALK) gene. These driver mutations typically are present in lung tumors found in never or light smokers. The addition of bevacizumab to carboplatin and paclitaxel in first-line treatment of non-squamous NSCLC showed improved survival compared to carboplatin and paclitaxel alone, 12.3 vs. 10.3 months respectively. Results from the POINTBREAK trial demonstrated that carboplatin + pemetrexed + bevacizumab is an alternative option to carboplatin + paclitaxel + bevacizumab, with comparable survival but less toxicity. In recent years, immunotherapy has emerged as a form of treatment that can lead to robust responses in a subset of patients. The PD-1 inhibitor nivolumab and the PD-L1 inhibitor atezolizumab have shown prolonged survival in comparison to docetaxel in patients who previously progressed with chemotherapy, irrespective of PD-L1 expression. Thus, this study combines immunotherapeutic agent atezolozumab with an ant-angiogenic agent, bevacizumab, and double platinum therapy (carboplatin and pemetrexed).

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.

What data supports the effectiveness of the drug combination of chemotherapy, bevacizumab, and immunotherapy for advanced non-small cell lung cancer?

Research shows that combining bevacizumab with chemotherapy, like pemetrexed and platinum-based drugs, has significant benefits for patients with advanced non-small cell lung cancer. Additionally, atezolizumab combined with bevacizumab and chemotherapy is considered a standard treatment, suggesting its effectiveness in improving patient outcomes. ^{1 2 3 4 5}

Is the combination of chemotherapy drugs and bevacizumab safe for treating advanced non-small cell lung cancer?

Research shows that the combination of chemotherapy drugs like carboplatin and pemetrexed with bevacizumab has been studied for safety in patients with advanced non-small cell lung cancer. These studies generally focus on how well patients tolerate the treatment and any side effects they experience, indicating that safety has been a key consideration in these trials. ^{6 7 8 9 10}

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

This drug combination is unique because it includes atezolizumab, an immunotherapy that helps the immune system fight cancer, along with bevacizumab, which targets blood vessels that supply the tumor, and traditional chemotherapy agents carboplatin and pemetrexed, offering a comprehensive approach to treating advanced non-small cell lung cancer. ^{3 6 11 12 13}

Research Team

Joseph Treat, MD

Principal Investigator

Fox Chase Cancer Center

Eligibility Criteria

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.

Trial Timeline

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

Treatment Details

Interventions

• Atezolizumab (Monoclonal Antibodies)
• Bevacizumab (Monoclonal Antibodies)
• Carboplatin (Alkylating agents)
• Pemetrexed (Anti-metabolites)

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).

Participant Groups

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

Who Is Running the Clinical Trial?

Fox Chase Cancer Center

Lead Sponsor

Trials

236

Recruited

39,300+

Dr. James Helstrom

Fox Chase Cancer Center

Chief Medical Officer since 2014

MD from University of Colorado School of Medicine, MBA from Washington University in St. Louis

Dr. Robert Uzzo

Fox Chase Cancer Center

Chief Executive Officer since 2022

MD from Cleveland Clinic, MBA

National Comprehensive Cancer Network

Collaborator

Trials

121

Recruited

7,400+

Crystal S. Denlinger

National Comprehensive Cancer Network

Chief Executive Officer since 2023

MD, FACP

Robert W. Carlson

National Comprehensive Cancer Network

Chief Medical Officer since 2013

MD

Findings from Research

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 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 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]

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]

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]

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]

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 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]

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 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]

References

1. Switzerland 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. [2022]

2. Thailand pubmed.ncbi.nlm.nih.gov

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

3. China 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). [2022]

4. China 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). [2023]

5. Ireland 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. [2021]

6. China pubmed.ncbi.nlm.nih.gov

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

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

Carboplatin/pemetrexed/bevacizumab in the treatment of patients with advanced non-small-cell lung cancer: a single-institution experience. [2022]

8. 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]

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

Pemetrexed versus gefitinib versus erlotinib in previously treated patients with non-small cell lung cancer. [2021]

10. England pubmed.ncbi.nlm.nih.gov

Phase II trial of pemetrexed disodium (ALIMTA, LY231514) in chemotherapy-naïve patients with advanced non-small-cell lung cancer. [2022]

11. United States 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. [2022]

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

Cost-effectiveness analysis of bevacizumab versus pemetrexed for advanced non-squamous NSCLC in Italy. [2022]

13. United States 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. [2021]