Chemotherapy + Immunotherapy vs. Immunotherapy for Advanced Lung Cancer

Recruiting at 322 trial locations

Age: 65+

Sex: Any

Trial Phase: Phase 3

Sponsor: National Cancer Institute (NCI)

Must not be taking: Immunosuppressants, Steroids

Disqualifiers: CNS metastases, Prior chemotherapy, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 10

304 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if adding chemotherapy to pembrolizumab, an immunotherapy, is more effective than using pembrolizumab alone for advanced lung cancer treatment. Pembrolizumab boosts the immune system to fight cancer, while chemotherapy directly targets cancer cells. The trial includes individuals with stage IIIB-IV non-small cell lung cancer who have not previously received such treatments and are managing the condition at an advanced stage. As a Phase 3 trial, this study serves as the final step before potential FDA approval, offering participants the opportunity to contribute to a treatment that could soon become widely available.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot be on immunosuppressive medication, including high doses of steroids, during the trial.

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

Research has shown that combining pembrolizumab with chemotherapy is generally well-tolerated by patients with advanced lung cancer. Studies have found this combination safe for many people. Some patients experienced side effects, but these were often manageable.

One study found that using pembrolizumab with chemotherapy helped patients live longer compared to chemotherapy alone. In terms of safety, while some side effects like tiredness and nausea occurred, serious issues were less common.

For pembrolizumab on its own, research indicates it is also well-tolerated. It has been used to treat lung cancer and other conditions with a good safety record. Common side effects include feeling tired and mild skin reactions, but these are usually not severe.

Overall, both treatment options have shown relative safety, with serious side effects being less frequent. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about pembrolizumab for advanced lung cancer because it leverages the power of the immune system to fight cancer cells. Unlike traditional chemotherapy, which directly attacks rapidly dividing cells, pembrolizumab is an immunotherapy that works by blocking the PD-1 pathway, allowing the immune system to better detect and destroy cancer cells. This mechanism can lead to more targeted and potentially less toxic treatment. The trial is also exploring the combination of pembrolizumab with chemotherapy, which may enhance the overall effectiveness by attacking cancer from multiple angles. This dual approach could offer a promising new option for patients with advanced lung cancer.

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

Research has shown that pembrolizumab, which participants in this trial may receive, can greatly improve outcomes for people with advanced lung cancer. In one study, 19.4% of patients with advanced non-small cell lung cancer (NSCLC) survived for five years after treatment with pembrolizumab. In this trial, some participants will receive pembrolizumab alone, while others will receive a combination of pembrolizumab and chemotherapy. Adding chemotherapy to pembrolizumab has also proven effective; another study found that this combination helped patients with metastatic squamous NSCLC live longer. Both treatment methods have demonstrated long-term success, offering hope to those with advanced lung cancer. ^{6 7 8 9 10}

Who Is on the Research Team?

Megan A Baumgart

Principal Investigator

ECOG-ACRIN Cancer Research Group

Are You a Good Fit for This Trial?

This trial is for older adults (70+) with stage IIIB-IV non-small cell lung cancer and a PD-L1 score of 1-49%. They must have adequate blood counts, not be candidates for chemo-radiation, and lack certain gene mutations. An ECOG status of 2 is required, indicating they can perform self-care but cannot work. Participants must agree to avoid fathering children during the study.

Inclusion Criteria

Absolute neutrophil count (ANC) ≥ 1,500/mcL (obtained within 14 days prior to Step 1 registration)

Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) ≤ 3.0 × institutional ULN (obtained within 14 days prior to Step 1 registration)

Patient must agree not to father children while on study and for 6 months after the last dose of protocol treatment

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction

Patients receive pembrolizumab IV over 30 minutes on day 1 of each cycle. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity.

12 weeks

4 visits (in-person)

Maintenance

Patients receive pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 21 or 42 days for 2 years in the absence of disease progression or unacceptable toxicity.

Up to 2 years

Every 3 weeks or 6 weeks (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment. Follow-up every 3 months if < 2 years from randomization and every 6 months if 2-5 years from Step 1 registration.

Up to 5 years

Every 3-6 months (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Carboplatin
• Nab-paclitaxel
• Paclitaxel
• Pembrolizumab
• Pemetrexed

Trial Overview The ACHIEVE trial compares adding chemotherapy (Pemetrexed, Nab-paclitaxel, Paclitaxel or Carboplatin) to immunotherapy (pembrolizumab) versus just immunotherapy alone in treating lung cancer. It will assess if combining these treatments helps stabilize the disease better than immunotherapy by itself.

How Is the Trial Designed?

Group I: Arm B (pembrolizumab, chemotherapy) Experimental Treatment 9 Interventions

See Detailed Description

Group II: Arm A (pembrolizumab) Active Control 5 Interventions

INDUCTION: Patients receive pembrolizumab IV over 30 minutes on day 1 of each cycle. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE: Patients receive pembrolizumab IV over 30 minutes on day 1 of each cycle. Cycles repeat every 21 or 42 days for 2 years in the absence of disease progression or unacceptable toxicity. Patients undergo MRI at baseline and CT and/or PET on the trial at baseline and throughout the trial.

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

Approved in United States as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in European Union as KEYTRUDA for:

• Head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1
• Melanoma
• Non-small cell lung cancer (NSCLC)
• Urothelial carcinoma
• Colorectal cancer
• Gastric cancer
• Hepatocellular carcinoma
• Renal cell carcinoma
• Cervical cancer
• Endometrial carcinoma

Approved in United Kingdom as KEYTRUDA for:

• Untreated metastatic or unresectable recurrent head and neck squamous cell carcinoma (HNSCC) with PD-L1 CPS ≥1

Who Is Running the Clinical Trial?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Pembrolizumab, an immunotherapy for advanced non-small-cell lung cancer (NSCLC), significantly improves progression-free and overall survival compared to traditional chemotherapy, with fewer side effects, particularly in patients with high PD-L1 expression (≥50%).

In combination with pemetrexed and carboplatin, pembrolizumab also enhances treatment effectiveness and maintains manageable toxicity, leading to a shift in first-line treatment strategies for advanced NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab as first-line therapy for metastatic non-small-cell lung cancer. Reck, M.[2018]

In a study of 24 patients with advanced non-small cell lung cancer (NSCLC) treated with pembrolizumab, the objective response rate was 45.8%, indicating that nearly half of the patients experienced a reduction in tumor size after treatment.

Pembrolizumab showed promising results even in PD-L1-negative patients, with a major pathological response of 75% and a pathological complete response of 50% in those who underwent surgery, suggesting its potential effectiveness across different patient profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluation of pembrolizumab for the treatment of advanced non-small cell lung cancer: a retrospective, single-centre, single-arm study. Guo, T., Ding, Y., Chen, L., et al.[2022]

Pembrolizumab, a PD-1 inhibitor, has demonstrated clinical effectiveness in treating various solid tumors, particularly in patients with PD-L1-positive non-small-cell lung cancer and unresectable/metastatic melanoma.

Early-phase trials and ongoing studies are focused on further confirming the clinical benefits of pembrolizumab in thoracic malignancies, highlighting its potential as a significant treatment option in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. Karim, S., Leighl, N.[2017]

In a study of 88 advanced melanoma patients treated with pembrolizumab, 81.8% experienced any-grade toxicities, with skin and gastrointestinal issues being the most common side effects.

Despite the high incidence of side effects, pembrolizumab was found to be well tolerated in real-world settings, and severe toxicities were manageable with systemic steroids.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Real-world experience with pembrolizumab toxicities in advanced melanoma patients: a single-center experience in the UK. So, AC., Board, RE.[2022]

In a phase II trial involving 15 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant treatment with pembrolizumab showed a major pathologic response in 27% of patients, indicating promising antitumor activity before surgery.

The treatment was found to be feasible and safe, with only 33% of patients experiencing moderate adverse events, and no postoperative mortality, suggesting that pembrolizumab does not compromise surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Eichhorn, F., Klotz, LV., Kriegsmann, M., et al.[2022]

Pembrolizumab (Keytruda) was approved by the FDA for treating metastatic non-small cell lung cancer (mNSCLC) in patients with tumors expressing PD-L1, showing significant improvements in overall survival (OS) and progression-free survival (PFS) in two major clinical trials with thousands of participants.

In the KEYNOTE-024 trial, pembrolizumab demonstrated a 40% reduction in the risk of death compared to chemotherapy, while in the KEYNOTE-010 trial, it also showed a significant survival advantage over chemotherapy in patients who had previously progressed on treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for Treatment of Metastatic Non-Small Cell Lung Cancer: First-Line Therapy and Beyond. Pai-Scherf, L., Blumenthal, GM., Li, H., et al.[2022]

Pembrolizumab, an immune checkpoint inhibitor, can cause pneumonitis in 1%-5% of patients, and this case report highlights an atypical presentation of this side effect in a patient with metastatic squamous cell carcinoma.

The patient was successfully treated with steroid therapy after ruling out other potential causes, leading to complete resolution of the pneumonitis, emphasizing the importance of recognizing and managing atypical cases of checkpoint inhibitor-pneumonitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recurrent and atypical immune checkpoint inhibitor-induced pneumonitis. Jeon, WJ., Nguyen, J., Castillo, DR., et al.[2023]

In the KEYNOTE-024 study involving 305 patients with untreated advanced non-small-cell lung cancer, pembrolizumab significantly improved overall survival (OS) compared to platinum-based chemotherapy, with a median OS of 30.0 months versus 14.2 months for chemotherapy.

Pembrolizumab also had a better safety profile, with fewer treatment-related severe adverse events (31.2% for pembrolizumab vs. 53.3% for chemotherapy), indicating it is a safer option for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Updated Analysis of KEYNOTE-024: Pembrolizumab Versus Platinum-Based Chemotherapy for Advanced Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score of 50% or Greater. Reck, M., Rodríguez-Abreu, D., Robinson, AG., et al.[2022]

In a study of 3,877 patients with advanced non-small-cell lung cancer (NSCLC) receiving pembrolizumab monotherapy, those who met eligibility criteria had significantly better overall survival (OS) compared to ineligible patients, with median OS of 16.3 months for eligible patients versus 8.2 months for ineligible patients.

The findings suggest that using an augmented population approach, which combines eligible and unknown patients, can enhance the analysis of real-world data, showing similar survival profiles and characteristics among these groups.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Augmenting Real-World Data Through Modeling Key Clinical Trial Eligibility Criteria: An Example of Patients With Non-small-Cell Lung Cancer Treated With Pembrolizumab. Jemielita, T., Li, XN., Burke, T., et al.[2021]

In a long-term study of 123 patients with advanced nonsquamous NSCLC, the combination of pembrolizumab with pemetrexed-carboplatin significantly improved the objective response rate (58% vs. 33%) and progression-free survival (24.5 months vs. 9.9 months) compared to chemotherapy alone.

Patients who completed 2 years of pembrolizumab treatment had a remarkable 92% survival rate at the data cutoff, indicating a durable clinical benefit, while the safety profile remained manageable with no new safety concerns identified.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-Term Overall Survival From KEYNOTE-021 Cohort G: Pemetrexed and Carboplatin With or Without Pembrolizumab as First-Line Therapy for Advanced Nonsquamous NSCLC. Awad, MM., Gadgeel, SM., Borghaei, H., et al.[2021]

This trial aims to compare the effectiveness of pembrolizumab combined with chemotherapy versus pembrolizumab alone in patients with advanced non-small-cell lung cancer who have high PD-L1 expression (≥50%).

The study expects that the combination treatment will lead to a lower risk of early disease progression and a higher objective tumor response, providing insights into long-term benefits for patients not eligible for other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

First-line pembrolizumab with or without platinum doublet chemotherapy in non-small-cell lung cancer patients with PD-L1 expression ≥50. Descourt, R., Chouaid, C., Pérol, M., et al.[2021]

In a study of 72 treatment-naïve patients with advanced non-small cell lung cancer (NSCLC) and high PD-L1 expression, pembrolizumab showed an objective response rate of 45.8%, with even higher rates of 70.0% in patients with pre-existing interstitial lung disease (ILD).

Patients with ILD had similar overall survival rates compared to those without ILD, suggesting that pembrolizumab can be safely administered to NSCLC patients with ILD without compromising their prognosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pre-existing interstitial lung disease does not affect prognosis in non-small cell lung cancer patients with PD-L1 expression ≥50% on first-line pembrolizumab. Yamaguchi, O., Kaira, K., Shinomiya, S., et al.[2021]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8636217/

The 5‐year outcomes of the KEYNOTE‐024 trial Pembrolizumab monotherapy could provide meaningful improved patient outcomes over platinum‐based chemotherapy for advanced NSCLC patients with PD‐L1 TPS ≥ 50%.

2. merck.com merck.com/news/five-year-data-for-mercks-keytruda-pembrolizumab-plus-chemotherapy-showed-sustained-survival-benefit-versus-chemotherapy-alone-in-two-studies-for-metastatic-non-small-cell-lung-cancer-nsclc/

Five-Year Data for Merck's KEYTRUDA® (pembrolizumab ... Five-year overall survival rate of 19.4% and 18.4% for KEYTRUDA plus chemotherapy in KEYNOTE-189 and KEYNOTE-407, respectively.

3. keytrudahcp.com keytrudahcp.com/efficacy/

Efficacy Data for KEYTRUDA® (pembrolizumab) Health care professionals may review efficacy data for KEYTRUDA® (pembrolizumab), browse the indications and select the corresponding KEYNOTE trials for ...

4. clinical-lung-cancer.com clinical-lung-cancer.com/article/S1525-7304(24)00081-0/fulltext

5-Year Real-World Outcomes With Frontline ... With 5-year follow-up in a real-world population, frontline pembrolizumab monotherapy continues to demonstrate long-term effectiveness.

5. ascopubs.org ascopubs.org/doi/10.1200/JCO.21.02885

Five-Year Outcomes With Pembrolizumab Versus ... KEYNOTE-042 is a randomized phase III study that showed significantly longer overall survival (OS) with pembrolizumab monotherapy versus platinum-based ...

6. ascopubs.org ascopubs.org/doi/10.1200/JCO.22.01990

5-Year Update of the Phase III KEYNOTE-407 Study Pembrolizumab plus chemotherapy maintained an OS and PFS benefit versus placebo plus chemotherapy in previously untreated, metastatic squamous NSCLC.

7. nejm.org nejm.org/doi/full/10.1056/NEJMoa1810865

Pembrolizumab plus Chemotherapy for Squamous Non– ... Squamous non–small-cell lung cancer (NSCLC) accounts for approximately 20 to 30% of all lung cancers and is associated with shorter survival ...

8. clinicaltrials.gov clinicaltrials.gov/study/NCT02039674

NCT02039674 | A Study of Pembrolizumab (MK-3475) in ... The purpose of this study is to determine the safety, tolerability, and efficacy of pembrolizumab (MK-3475) in combination with chemotherapy or immunotherapy

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9989798/

Pembrolizumab plus pemetrexed-carboplatin combination ... This real-life study aimed to assess efficacy and safety of carboplatin-pemetrexed plus pembrolizumab in advanced non-squamous non-small cell lung cancer.

10. merck.com merck.com/news/mercks-keytruda-pembrolizumab-plus-pemetrexed-and-carboplatin-pem-carbo-demonstrated-continued-benefit-in-overall-response-rates-and-progression-free-survival-compared-to-pem-carbo/

Merck's KEYTRUDA® (pembrolizumab) Plus Pemetrexed ... “Lung cancer is one of the most common and devastating cancers, and these additional data confirm that KEYTRUDA in combination with pemetrexed and carboplatin ...