Combination Chemotherapy and Immunotherapy for Non-Small Cell Lung Cancer

(NeoCOAST-2 Trial)

Recruiting in Palo Alto (17 mi)

+69 other locations

Overseen by Tina Cascone

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2

Recruiting

Sponsor: AstraZeneca

Must not be taking: Immunosuppressants, Chemotherapy, Biologics, others

Disqualifiers: EGFR mutations, ALK translocations, Autoimmune disorders, others

No Placebo Group

Prior Safety Data

Breakthrough Therapy

Trial Summary

What is the purpose of this trial?

The study is intended to assess the safety and efficacy of perioperative treatment with Durvalumab in combination with Oleclumab, Monalizumab, or AZD0171 and platinum doublet chemotherapy (CTX); or Volrustomig or Rilvegostomig in combination with CTX; or Datopotamab deruxtecan (Dato-DXd) in combination with Durvalumab or Rilvegostomig and single agent platinum chemotherapy in participants with resectable, early-stage non-small cell lung cancer.

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

The trial does not specify if you need to stop your current medications, but you cannot use immunosuppressive medication within 14 days before starting the study. It's best to discuss your current medications with the trial team.

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

Research shows that combining pemetrexed with platinum-based drugs like cisplatin or carboplatin improves survival in non-small cell lung cancer patients. Additionally, adding pembrolizumab, an immunotherapy drug, to this combination further enhances survival rates, regardless of specific tumor characteristics. ^{1 2 3 4 5}

Is the combination of chemotherapy and immunotherapy for non-small cell lung cancer safe?

The combination of pemetrexed with cisplatin or carboplatin has been studied for safety in non-small cell lung cancer patients. Common side effects include fatigue, nausea, and blood-related issues like neutropenia (low white blood cell count). Some serious side effects, such as skin reactions, have been reported, but taking vitamins and steroids can help reduce these risks. ^{1 6 7 8 9}

How is the combination chemotherapy and immunotherapy treatment for non-small cell lung cancer different from other treatments?

This treatment is unique because it combines chemotherapy, which directly kills cancer cells, with immunotherapy, which helps the immune system fight cancer. This dual approach may offer a more comprehensive attack on the cancer compared to traditional chemotherapy alone. ^{1 10 11 12 13}

Eligibility Criteria

This trial is for newly diagnosed NSCLC patients with resectable disease stages IIA-IIIB, who have good organ and bone marrow function, can provide recent tumor samples to check certain biomarkers, and have a performance status of 0 or 1. It excludes those with autoimmune disorders, prior cancer treatments, planned lung surgeries like pneumonectomy, EGFR mutations/ALK translocations, heart issues including QTcF ≥470 ms, previous immune therapy or specific ADCs use.

Inclusion Criteria

I am fully active or can carry out light work.

My organs and bone marrow are working well.

I can provide recent (≤ 6 months old) tumor samples for PD-L1, EGFR, or ALK status testing.

Exclusion Criteria

I do not have any active or uncontrolled infections.

I am scheduled for radiotherapy before surgery as part of my treatment plan.

I am not currently on any cancer treatments like chemotherapy or hormone therapy.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Neoadjuvant Treatment

Participants receive neoadjuvant treatment with various combinations of Durvalumab, Oleclumab, Monalizumab, Volrustomig, Rilvegostomig, AZD0171, Dato-DXd, and chemotherapy

6-8 weeks

Surgery

Participants undergo surgical resection of the tumor

1 week

Adjuvant Treatment

Participants receive adjuvant treatment with various combinations of Durvalumab, Oleclumab, Monalizumab, Volrustomig, Rilvegostomig, AZD0171, and Dato-DXd

12-24 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Treatment Details

Interventions

• Carboplatin (Chemotherapy)
• Cisplatin (Chemotherapy)
• Dato-DXd (Antibody-Drug Conjugate)
• Durvalumab (Monoclonal Antibodies)
• MEDI5752 (Monoclonal Antibodies)
• Monalizumab (Monoclonal Antibodies)
• Oleclumab (Monoclonal Antibodies)
• Paclitaxel (Chemotherapy)
• Pemetrexed (Chemotherapy)

Trial Overview The study tests the safety and effectiveness of perioperative treatment combining Durvalumab with Oleclumab/Monalizumab/AZD0171 plus platinum-based chemo; MEDI5752 plus platinum chemo; or Dato-DXd with Durvalumab and single-agent platinum chemo in early-stage NSCLC that can be surgically removed.

Participant Groups

Group I: Arm 7: Dato-DXd + Rilvegostomig + single agent platinum Experimental Treatment 4 Interventions

Participants will receive Dato-DXd + Rilvegostomig + single agent platinum as neoadjuvant treatment and Rilvegostomig as adjuvant treatment. Participants will receive one of the following chemotherapy regimens, based on physician choice of as part of their treatment regimen prior to surgery: Carboplatin or Cisplatin

Group II: Arm 6: Rilvegostomig + CTX Experimental Treatment 4 Interventions

Participants will receive Rilvegostomig + CTX as neoadjuvant treatment and Rilvegostomig as adjuvant treatment. Participants will receive one of the following chemotherapy regimens, based on the tumour histology and Investigator's discretion, as part of their treatment regimen prior to surgery: Carboplatin/Paclitaxel Pemetrexed/Cisplatin Pemetrexed/Carboplatin

Group III: Arm 5: AZD0171 + durvalumab + CTX Experimental Treatment 5 Interventions

Participants will receive AZD0171 + durvalumab + CTX as neoadjuvant treatment and AZD0171 + durvalumab as adjuvant treatment. Participants will receive one of the following chemotherapy regimens, based on the tumour histology and Investigator's discretion, as part of their treatment regimen prior to surgery: Carboplatin/Paclitaxel Pemetrexed/Cisplatin Pemetrexed/Carboplatin

Group IV: Arm 4: Dato-DXd + durvalumab + single agent platinum Experimental Treatment 4 Interventions

Participants will receive Dato-DXd + durvalumab + single agent platinum as neoadjuvant treatment and durvalumab as adjuvant treatment. Participants will receive one of the following chemotherapy regimens, based on physician choice of as part of their treatment regimen prior to surgery: Carboplatin or Cisplatin

Group V: Arm 3: Volrustomig (Dose Exploration) + CTX Experimental Treatment 4 Interventions

Participants will receive Volrustomig + CTX as neoadjuvant treatment and Volrustomig as adjuvant treatment. Participants will receive one of the following chemotherapy regimens, based on the tumour histology and Investigator's discretion, as part of their treatment regimen prior to surgery: Carboplatin/Paclitaxel Pemetrexed/Cisplatin Pemetrexed/Carboplatin

Group VI: Arm 2: Monalizumab + Durvalumab + CTX Experimental Treatment 5 Interventions

Participants will receive Durvalumab + Monalizumab + CTX as neoadjuvant treatment and Durvalumab + Monalizumab as adjuvant treatment. Participants will receive one of the following chemotherapy regimens, based on the tumour histology and Investigator's discretion, as part of their treatment regimen prior to surgery: Carboplatin/Paclitaxel Pemetrexed/Cisplatin Pemetrexed/Carboplatin

Group VII: Arm 1: Oleclumab + Durvalumab + Platinum doublet chemotherapy (CTX) Experimental Treatment 5 Interventions

Participants will receive Durvalumab + Oleclumab + CTX as neoadjuvant treatment and Durvalumab + Oleclumab as adjuvant treatment. Participants will receive one of the following chemotherapy regimens, based on the tumour histology and Investigator's discretion, as part of their treatment regimen prior to surgery: Carboplatin/Paclitaxel Pemetrexed/Cisplatin Pemetrexed/Carboplatin

Find a Clinic Near You

Research Locations Nearby Select from list below to view details:

Research Site Omaha, NE

Research Site Buffalo, NY

Research Site Memphis, TN

Research Site Seattle, WA

More Trial Locations

Who Is Running the Clinical Trial?

AstraZeneca Lead Sponsor

Parexel Industry Sponsor

References

1. England pubmed.ncbi.nlm.nih.gov

Pemetrexed plus cisplatin/carboplatin in previously treated locally advanced or metastatic non-small cell lung cancer patients. [2021] The objective of this study was to evaluate the efficacy and safety of pemetrexed plus cisplatin/carboplatin in locally advanced or metastatic non-small cell lung cancer (NSCLC) patients previously treated with platinum-based chemotherapy.

2. England pubmed.ncbi.nlm.nih.gov

Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: protocol-specified final analysis from KEYNOTE-189. [2022] In the phase III KEYNOTE-189 study (NCT02578680), pembrolizumab plus pemetrexed and platinum-based chemotherapy (pemetrexed-platinum) significantly improved overall survival (OS) and progression-free survival (PFS) in patients with previously untreated metastatic nonsquamous non-small-cell lung cancer (NSCLC) versus placebo plus pemetrexed-platinum. We report updated efficacy outcomes from the protocol-specified final analysis, including outcomes in patients who crossed over to pembrolizumab from pemetrexed-platinum and in patients who completed 35 cycles (∼2 years) of pembrolizumab.

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

Combined Checkpoint Inhibition and Chemotherapy: New Era of 1st-Line Treatment for Non-Small-Cell Lung Cancer. [2020] Platinum-based chemotherapy has long been the first-line treatment of choice for metastatic non-small-cell lung cancer (NSCLC) patients who lack targetable gene mutations. The arrival of checkpoint blockade has led to a vast shift in the treatment landscape of NSCLC. Among NSCLC patients with PD-L1 expression in ≥50% of tumor cells, treatment with pembrolizumab leads to a superior progression-free and overall survival compared to platinum-doublet chemotherapy in the first-line setting. Furthermore, the addition of pembrolizumab to standard chemotherapy of pemetrexed and a platinum-based drug resulted in significant longer progression-free survival and overall survival irrespective to PD-L1 expression. In this review, we focus on the molecular rationale for the combination therapy and the results of completed clinical studies.

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

Pemetrexed (Alimta): a new antifolate for non-small-cell lung cancer. [2017] Pemetrexed (Alimta) is a novel multitargeted antifolate that has activity against non-small-cell lung cancer (NSCLC). As a single agent, the response rate is 16%-23%. As second-line therapy, it has a 5% and 14% response rate with pemetrexed in NSCLC patients who have had prior cisplatin or nonplatinum chemotherapy, respectively. Pemetrexed combined with cisplatin has a response rate of 38.9%-44.8%, with a median survival of 8.9-10.9 months. Pemetrexed plus gemcitabine in NSCLC has a response rate of less than 25%. The major toxicity associated with pemetrexed is neutropenia, which may be reduced with vitamin B12 and folate nutritional supplement. Additional studies with pemetrexed in combination with other agents are needed for the treatment of NSCLC patients.

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

Updated Analysis From KEYNOTE-189: Pembrolizumab or Placebo Plus Pemetrexed and Platinum for Previously Untreated Metastatic Nonsquamous Non-Small-Cell Lung Cancer. [2021] In KEYNOTE-189, first-line pembrolizumab plus pemetrexed-platinum significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo plus pemetrexed-platinum in patients with metastatic nonsquamous non‒small-cell lung cancer (NSCLC), irrespective of tumor programmed death-ligand 1 (PD-L1) expression. We report an updated analysis from KEYNOTE-189 (ClinicalTrials.gov: NCT02578680).

6. Netherlands pubmed.ncbi.nlm.nih.gov

Pemetrexed and carboplatin combination therapy followed by pemetrexed maintenance in Japanese patients with non-squamous non-small cell lung cancer: A subgroup analysis of elderly patients. [2022] The combination of pemetrexed and carboplatin is commonly used for the treatment of advanced non-squamous non-small cell lung cancer (NSCLC), mainly because it is comparatively effective and less toxic than other platinum-doublet therapies. Using the JMII (JACAL) study, we report the efficacy and safety of this treatment followed by pemetrexed maintenance in the elderly population (≥70 years of age).

7. 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] PRONOUNCE compared the efficacy and safety of pemetrexed+carboplatin followed by pemetrexed (Pem+Cb) with paclitaxel+carboplatin+bevacizumab followed by bevacizumab (Pac+Cb+Bev) in patients with advanced nonsquamous non-small-cell lung cancer (NSCLC).

8. Switzerland pubmed.ncbi.nlm.nih.gov

Toxic epidermal necrolysis after pemetrexed and cisplatin for non-small cell lung cancer in a patient with sharp syndrome. [2015] Pemetrexed is an antifolate drug approved for maintenance and second-line therapy, and, in combination with cisplatin, for first-line treatment of advanced nonsquamous non-small cell lung cancer. The side-effect profile includes fatigue, hematological and gastrointestinal toxicity, an increase in hepatic enzymes, sensory neuropathy, and pulmonary and cutaneous toxicity in various degrees.

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

FDA drug approval summaries: pemetrexed (Alimta). [2022] The purpose of this report is to summarize information on pemetrexed (LY231514; MTA; Alimta; Eli Lilly and Company; Indianapolis, IN), a drug recently approved by the U.S. Food and Drug Administration (FDA). The review of the efficacy and safety of pemetrexed is summarized below. Pemetrexed is a pyrrolopyrimidine antifolate. It inhibits thymidylate synthase, glycinamide ribonucleotide formyltransferase, and dihydrofolate reductase. In a single, randomized, single-blind, multicenter phase III trial, the efficacy and safety of pemetrexed combined with cisplatin (Platinol; Bristol-Myers Squibb; Princeton, NJ) were compared with those of single-agent cisplatin in 448 patients with malignant pleural mesothelioma. Two hundred twenty-six patients were randomized to receive pemetrexed and cisplatin, while 222 patients were randomized to receive cisplatin alone. The primary study end point was survival. Median survival times were 12.1 months for the pemetrexed plus cisplatin treated arm and 9.3 months for the cisplatin alone arm. Pemetrexed causes myelosuppression. The most common adverse events were neutropenia, fatigue, leukopenia, nausea, dyspnea, and vomiting. On February 4, 2004, pemetrexed was approved by the FDA in combination with cisplatin for the treatment of patients with malignant pleural mesothelioma whose disease is unresectable or who are otherwise not candidates for curative surgery. The recommended dose of pemetrexed is 500 mg/m(2) administered as an i.v. infusion over 10 minutes on day 1 of each 21-day cycle together with cisplatin at a dose of 75 mg/m(2) infused over 2 hours beginning 30 minutes after the pemetrexed infusion. Patients must receive oral folic acid and vitamin B(12) injections prior to the start of therapy and continue these during therapy to reduce severe toxicities. Patients should also receive corticosteroids with chemotherapy to reduce the risk of skin rashes. Approval was based on superior survival as a clinical benefit.

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

A randomized phase II study of pemetrexed in combination with cisplatin or carboplatin as first-line therapy for patients with locally advanced or metastatic non-small-cell lung cancer. [2022] Pemetrexed plus cisplatin was approved for first-line treatment of non-small-cell lung cancer (NSCLC) in patients with nonsquamous histology after initiation of this study. This phase II study evaluated pemetrexed plus cisplatin and pemetrexed plus carboplatin as first-line treatments for stage IIIB/IV NSCLC.

11. Switzerland pubmed.ncbi.nlm.nih.gov

An Open-Label Randomized Controlled Trial Comparing the Efficacy and Safety of Pemetrexed-Carboplatin versus (Weekly) Paclitaxel-Carboplatin as First-Line Chemotherapy in Advanced Non-Squamous Non-Small Cell Lung Cancer. [2021] Before the approval of first-line immune checkpoint inhibitors, platinum doublets were the standard of care in patients with treatment-naïve advanced non-small cell lung cancer (NSCLC) without targetable driver mutations. Pemetrexed-platinum combinations are preferred in non-squamous NSCLC. However, there has been no direct comparison to paclitaxel-carboplatin.

12. Switzerland pubmed.ncbi.nlm.nih.gov

Toxic epidermal necrolysis related to pemetrexed and carboplatin with vitamin B12 and folic acid supplementation for advanced non-small cell lung cancer. [2015] Pemetrexed is a multitargeted antifolate initially approved as a single agent for the second-line treatment of locally advanced or metastatic non-small cell lung cancer and more recently in the first-line setting combined with cisplatin. The combination of pemetrexed with carboplatin has been tested in several phase II clinical trials showing interesting antitumour activity with mild toxicity. Supplementation with folic acid and vitamin B12 during treatment with pemetrexed is recommended to reduce potential haematological and gastrointestinal adverse events.

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

Randomized Phase III Study of Docetaxel Plus Cisplatin Versus Pemetrexed Plus Cisplatin as First-line Treatment of Nonsquamous Non-Small-cell Lung Cancer: A TRAIL Trial. [2018] To date, no prospective phase III trials have directly compared the efficacy of pemetrexed plus cisplatin (Pem-Cis) with docetaxel plus cisplatin (Doc-Cis) in patients with nonsquamous non-small-cell lung cancer.