Combination Therapy for Lung Cancer

Recruiting at 40 trial locations

Overseen By Reference Study ID Number: ML41591 https://forpatients.roche.com/

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Genentech, Inc.

Must not be taking: Chemotherapy, Immunotherapy, Radiotherapy, others

Disqualifiers: Prior lung cancer, HIV, 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

125 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial will evaluate the efficacy and safety of various therapies in patients with Stage IB, IIA, IIB, IIIA, or selected IIIB resectable and untreated non-small cell lung cancer (NSCLC) tumors that meet protocol-specified biomarker criteria

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of the drug combination therapy for lung cancer?

The combination of atezolizumab (an immune-checkpoint inhibitor) with stereotactic ablative radiotherapy (SABR) showed early responses in 17% of patients with early-stage non-small cell lung cancer, suggesting potential benefits. Additionally, the combination of a PD-L1 inhibitor with chemotherapy improved survival in small cell lung cancer, indicating that similar combinations might be effective in other lung cancer types. ^{1 2 3 4 5}

Is the combination therapy for lung cancer generally safe in humans?

Alectinib, a drug used in combination therapy for lung cancer, is generally well tolerated but can cause serious side effects, including severe skin reactions and liver issues. It's important for patients to be closely monitored for these potential adverse effects. ^{6 7 8 9 10}

What makes this lung cancer treatment unique?

This treatment is unique because it combines multiple therapies, including targeted drugs like Alectinib and Entrectinib, immunotherapy with Atezolizumab, and traditional chemotherapy, along with surgical and radiation options. This comprehensive approach aims to target different aspects of lung cancer, potentially improving outcomes compared to standard treatments that typically use fewer components. ^{1 5 11 12 13}

Research Team

Clinical Trials

Principal Investigator

Hoffmann-La Roche

Eligibility Criteria

This trial is for adults with resectable, untreated Stage IB-III non-small cell lung cancer (NSCLC) that have specific biomarkers. They must be medically fit for surgery, have good organ function and performance status, and not have had any prior lung cancer treatments in the last 2 years. Participants should agree to use contraception and cannot join if they've had major surgery recently or other cancers within 3 years.

Inclusion Criteria

You should not have hepatitis C virus (HCV) or it should not be active in your body.

I am fully active or can carry out light work.

My blood and organs are functioning well.

Exclusion Criteria

Pregnant or lactating, or intending to become pregnant during the study

I haven't had lung cancer treatment in the last 2 years.

I haven't had any other cancers in the last 3 years, except for those with a low risk and curable outcome.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Neoadjuvant Treatment

Participants receive neoadjuvant treatment specific to their cohort (e.g., atezolizumab, pralsetinib, entrectinib, etc.) for up to 8 weeks before surgical resection

8 weeks

Surgical Resection

Participants undergo surgical resection per standard of care

1 week

Adjuvant Treatment

Participants receive adjuvant treatment specific to their cohort, including chemotherapy and/or targeted therapies for up to 2 years

Up to 2 years

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Alectinib
• Atezolizumab
• Chemotherapy
• Cobimetinib
• Entrectinib
• Pralsetinib
• Resection
• SBRT
• Vemurafenib

Trial Overview The study tests multiple therapies including Divarasib, Vemurafenib, Alectinib, Chemotherapy, Resection (surgery), Cobimetinib, Pralsetinib, SBRT (a type of radiation therapy), Atezolizumab (immunotherapy), and Entrectinib on patients with NSCLC who meet certain genetic criteria. The goal is to see which treatment works best.

Participant Groups

Group I: ROS 1 Cohort Experimental Treatment 3 Interventions

Participants will receive up to 8 weeks of entrectinib neoadjuvant treatment before undergoing surgical resection per standard of care. All participants that undergo surgical resection and whose tumors have pathological response or lack radiographic progression will be eligible for the Adjuvant Treatment Phase with entrectinib. Adjuvant therapy will consist of 4 cycles of chemotherapy followed by up to 2 years of entrectinib.

Group II: RET Cohort (Enrollment closed) Experimental Treatment 3 Interventions

Participants will receive up to 8 weeks of pralsetinib neoadjuvant treatment before undergoing surgical resection per standard of care. All participants that undergo surgical resection and whose tumors have pathological response or lack radiographic progression will be eligible for the Adjuvant Treatment Phase with pralsetinib. Adjuvant therapy will consist of 4 cycles of chemotherapy followed by up to 2 years of pralsetinib. Enrollment closed.

Group III: PD-L1 Cohort Experimental Treatment 3 Interventions

Participants with positive PD-L1 in ≥1% tumor cells will receive 4 cycles of atezolizumab neoadjuvant treatment. During neoadjuvant Cycle 1 of atezolizumab, patients will also receive low-dose SBRT (8Gy X 3). Adjuvant treatment consists of SOC treatment as determined by the investigator, per NCCN guidelines

Group IV: NTRK Cohort Experimental Treatment 3 Interventions

Participants will receive up to 8 weeks of entrectinib neoadjuvant treatment before undergoing surgical resection per standard of care. All participants that undergo surgical resection and whose tumors have pathological response or lack radiographic progression will be eligible for the Adjuvant Treatment Phase with entrectinib. Adjuvant therapy will consist of 4 cycles of chemotherapy followed by up to 2 years of entrectinib.

Group V: KRAS G12C Cohort Experimental Treatment 2 Interventions

Participants will receive up to 8 weeks of divarasib as neoadjuvant treatment before undergoing surgical resection per standard of care. PD-L1 negative patients whose tumors have pathological response or lack radiographic progression will be have the option of continuing divarasib for up to 2 years as adjuvant therapy. For patients who test positive PD-L1, they will have the option to receive Atezolizumab for up to 16 cycles.

Group VI: BRAF Cohort (Enrollment closed, no participants enrolled) Experimental Treatment 4 Interventions

Participants will receive up to 8 weeks of vemurafenib plus cobimetinib neoadjuvant treatment before undergoing surgical resection per standard of care. All participants that undergo surgical resection and whose tumors have pathological response or lack radiographic progression will be eligible for the Adjuvant Treatment Phase with vemurafenib plus cobimetinib. Adjuvant therapy will consist of 4 cycles of chemotherapy followed by up to 2 years of of vemurafenib plus cobimetinib. Enrollment closed.

Group VII: ALK Cohort Experimental Treatment 3 Interventions

Participants will receive up to 8 weeks of alectinib neoadjuvant treatment before undergoing surgical resection per standard of care. All participants that undergo surgical resection and whose tumors have pathological response or lack radiographic progression will be eligible for the Adjuvant Treatment Phase with alectinib. Adjuvant therapy will consist of 4 cycles of chemotherapy followed by up to 2 years of alectinib.

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

Approved in United States as Alecensa for:

• Metastatic ALK-positive non-small cell lung cancer (NSCLC)
• Adjuvant treatment following tumor resection in patients with ALK-positive NSCLC

Approved in European Union as Alecensa for:

• Metastatic ALK-positive non-small cell lung cancer (NSCLC)
• Adjuvant treatment following tumor resection in patients with ALK-positive NSCLC

Who Is Running the Clinical Trial?

Genentech, Inc.

Lead Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Blueprint Medicines Corporation

Industry Sponsor

Trials

31

Recruited

6,000+

Chugai Pharmaceutical Co.

Collaborator

Trials

4

Recruited

380+

Hoffmann-La Roche

Industry Sponsor

Trials

2,482

Recruited

1,107,000+

Headquarters

Basel, Switzerland

Known For

Precision medicine

Top Products

Avastin, Herceptin, Rituxan, Accu-Chek

Dr. Levi Garraway

Hoffmann-La Roche

Chief Medical Officer since 2019

MD from the University of Basel

Dr. Thomas Schinecker

Hoffmann-La Roche

Chief Executive Officer since 2023

PhD in Molecular Biology from New York University

Findings from Research

Adjuvant platinum-based chemotherapy is the standard treatment for patients with resected non-small-cell lung cancer (NSCLC) stage IB to IIIA, but many still face disease recurrence, highlighting the need for more effective therapies.

The ALCHEMIST trial is investigating the efficacy of pembrolizumab, a PD-1 inhibitor, in combination with chemotherapy to potentially improve outcomes compared to standard chemotherapy alone, with the aim of reducing recurrence rates in NSCLC patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Integration of immunotherapy into adjuvant therapy for resected non-small-cell lung cancer: ALCHEMIST chemo-IO (ACCIO). Sands, JM., Mandrekar, SJ., Kozono, D., et al.[2022]

In a phase 2 study involving 216 patients with stage III non-small cell lung cancer (NSCLC), the combination of pembrolizumab and concurrent chemoradiation therapy (cCRT) showed a high objective response rate of approximately 70.5% in cohort A and 70.6% in cohort B, indicating strong antitumor activity.

The treatment was associated with manageable safety, with grade 3 or higher pneumonitis occurring in 8.0% of cohort A and 6.9% of cohort B, suggesting that while there are risks, the benefits of this treatment approach may outweigh them for patients with locally advanced NSCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab Plus Concurrent Chemoradiation Therapy in Patients With Unresectable, Locally Advanced, Stage III Non-Small Cell Lung Cancer: The Phase 2 KEYNOTE-799 Nonrandomized Trial. Jabbour, SK., Lee, KH., Frost, N., et al.[2022]

A phase I trial presented in 2015 indicates that rovalpituzumab tesirine, an experimental antibody-drug conjugate, shows potential effectiveness against recurrent small cell lung cancer, a type of cancer with limited treatment options.

This trial highlights the promise of rovalpituzumab tesirine as a new therapeutic approach for patients suffering from this challenging form of lung cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

ADC Shows Effectiveness in SCLC. [2015]

In a phase I study involving 20 patients with early-stage non-small cell lung cancer, the combination of stereotactic ablative radiotherapy (SABR) and the immune-checkpoint inhibitor atezolizumab was well tolerated, with the maximum tolerated dose established at 1200 mg.

Early efficacy signals were observed, with 17% of patients showing responses after two cycles of atezolizumab before starting SABR, and specific biomarkers indicating T cell activation were found to be predictive of treatment benefit.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Atezolizumab plus stereotactic ablative radiotherapy for medically inoperable patients with early-stage non-small cell lung cancer: a multi-institutional phase I trial. Monjazeb, AM., Daly, ME., Luxardi, G., et al.[2023]

The combination treatment of benmelstobart (a PD-L1 inhibitor), anlotinib (an angiogenesis inhibitor), and the chemotherapies etoposide and carboplatin significantly improved progression-free survival and overall survival in patients with newly diagnosed extensive-stage small cell lung cancer.

This combination therapy resulted in longer survival rates than any previously reported trials for this patient population, indicating a potentially more effective treatment strategy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Benmelstobart Ups ES-SCLC Survival. [2023]

Alectinib, while effective for treating advanced non-small-cell lung cancer (NSCLC) with ALK rearrangements, can lead to serious side effects such as grade 4 hyperbilirubinemia, as seen in a patient after five months of treatment.

After discontinuing alectinib and using an artificial liver support system to manage the hyperbilirubinemia, the patient was successfully treated with ensartinib, achieving stable disease without recurrence of hyperbilirubinemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful Treatment with Ensartinib After Alectinib-induced Hyperbilirubinemia in ALK-Positive NSCLC. Peng, L., Xiao, K., Cui, J., et al.[2022]

Alectinib, a second-generation ALK-tyrosine kinase inhibitor, is generally considered safer than other TKIs and is being tested for RET-rearranged non-small-cell lung cancer (NSCLC).

However, two patients experienced severe skin toxicity after receiving alectinib following treatment with an immune checkpoint inhibitor (ICI), highlighting the need for careful monitoring of adverse effects when combining these therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Severe Skin Toxicity Caused by Sequential Anti-PD-1 Antibody and Alectinib in Non-small-cell Lung Cancer: A Report of Two Cases and a Literature Review. Nishiyama, A., Hattori, Y., Takeuchi, S., et al.[2022]

Alectinib is an effective next-generation ALK inhibitor for patients with metastatic ALK-positive non-small-cell lung cancer (NSCLC), showing improved progression-free survival and a reduction in brain metastases compared to crizotinib, especially in patients who are intolerant or have progressed on crizotinib.

Common side effects of alectinib include fatigue, constipation, and peripheral edema, with more serious effects being increases in liver enzymes and creatine phosphokinase, indicating it is generally well-tolerated in clinical use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alectinib for advanced ALK-positive non-small-cell lung cancer. Ly, AC., Olin, JL., Smith, MB.[2019]

A study of 130 treatment courses in 111 patients revealed that safety monitoring activities (SMAs) for EGFR and ALK inhibitors were inconsistently conducted, with prevalence ranging from 10.0% to 84.6%, and 31.5% of courses had no SMAs performed.

EGFR inhibitors were associated with a higher likelihood of SMAs being conducted compared to ALK inhibitors, highlighting the need for clinicians to closely follow FDA guidelines to ensure patient safety and monitor for serious adverse events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety Monitoring Activity During EGFR or Anaplastic Lymphoma Kinase Inhibitor Therapy for Patients With Lung Cancer. Singh, AM., Rubiera-Pebe, R., Ahmad, Y., et al.[2023]

Alectinib, a tyrosine kinase inhibitor, was successfully administered via percutaneous gastrostomy to a 90-year-old patient with swallowing disorders due to anaplastic lymphoma kinase-rearranged lung cancer, leading to significant clinical and radiological improvements.

After 2 months of treatment, the patient showed a 60% reduction in tumor lesions and a notable increase in cognitive function, demonstrating that enteral administration of TKIs can be an effective option for elderly patients with impaired conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enteral administration of alectinib for ALK-positive non-small cell lung cancer in an elderly patient: A case report. Thomas, QD., Pautas, M., Guilhaume, MN., et al.[2023]

A variety of new agents, including taxanes, gemcitabine, and irinotecan, have shown promise in early clinical studies for treating non-small-cell lung cancer (NSCLC), indicating potential for improved treatment options.

Cisplatin remains a key component in combination therapies for NSCLC, being tested alongside these new agents, radiation, and surgery in numerous trials to enhance treatment efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Chemotherapy in metastatic non-small-cell lung cancer. Sandler, A.[2022]

Current standard treatment for advanced non-small-cell lung cancer involves doublet chemotherapy, which has shown 1-year survival rates of approximately 35% and 2-year survival rates of about 15%.

Preliminary studies indicate that triplet therapy may enhance survival rates compared to double therapy, with toxicity rates being low enough to support the development of these three-drug combinations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Triplet combination chemotherapy and targeted therapy regimens. Bunn, PA.[2005]

Recent advancements in lung cancer therapy have led to the identification of actionable mutations, such as those in EGFR and translocations in ALK and ROS1, which allow for targeted oral treatments that show excellent tumor responses and manageable side effects.

The review discusses various treatment options and clinical trials for other oncogenic alterations affecting receptor tyrosine kinases and components of the RAS-RAF-MEK signaling pathway, expanding the potential for personalized medicine in lung cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alterations in genes other than EGFR/ALK/ROS1 in non-small cell lung cancer: trials and treatment options. Desai, A., Menon, SP., Dy, GK.[2020]

References

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

Integration of immunotherapy into adjuvant therapy for resected non-small-cell lung cancer: ALCHEMIST chemo-IO (ACCIO). [2022]

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

Pembrolizumab Plus Concurrent Chemoradiation Therapy in Patients With Unresectable, Locally Advanced, Stage III Non-Small Cell Lung Cancer: The Phase 2 KEYNOTE-799 Nonrandomized Trial. [2022]

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

ADC Shows Effectiveness in SCLC. [2015]

4. England pubmed.ncbi.nlm.nih.gov

Atezolizumab plus stereotactic ablative radiotherapy for medically inoperable patients with early-stage non-small cell lung cancer: a multi-institutional phase I trial. [2023]

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

Benmelstobart Ups ES-SCLC Survival. [2023]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Successful Treatment with Ensartinib After Alectinib-induced Hyperbilirubinemia in ALK-Positive NSCLC. [2022]

7. Japan pubmed.ncbi.nlm.nih.gov

Severe Skin Toxicity Caused by Sequential Anti-PD-1 Antibody and Alectinib in Non-small-cell Lung Cancer: A Report of Two Cases and a Literature Review. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Alectinib for advanced ALK-positive non-small-cell lung cancer. [2019]

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

Safety Monitoring Activity During EGFR or Anaplastic Lymphoma Kinase Inhibitor Therapy for Patients With Lung Cancer. [2023]

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

Enteral administration of alectinib for ALK-positive non-small cell lung cancer in an elderly patient: A case report. [2023]

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

Chemotherapy in metastatic non-small-cell lung cancer. [2022]

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

Triplet combination chemotherapy and targeted therapy regimens. [2005]

13. China pubmed.ncbi.nlm.nih.gov

Alterations in genes other than EGFR/ALK/ROS1 in non-small cell lung cancer: trials and treatment options. [2020]