Combination Therapy for Lung Cancer

Recruiting at 37 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

99 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of different treatments for people with early-stage non-small cell lung cancer (NSCLC) that can still be surgically removed. The study aims to determine if these treatments can safely reduce cancer growth and improve outcomes before and after surgery. It involves various drugs and procedures, including chemotherapy and targeted therapies such as Alectinib, Atezolizumab, Cobimetinib, Entrectinib, Pralsetinib, and Vemurafenib, each targeting different genetic markers in the tumor. People with newly diagnosed, early-stage NSCLC that can be surgically removed and have certain genetic features might be suitable for this trial. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group of participants.

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.

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

Previous research has shown varying safety levels for the treatments tested in this trial. Alectinib is usually well-tolerated, with most side effects being mild. Some patients have experienced kidney issues, but serious problems are rare. Entrectinib, approved for certain lung cancers, has known side effects like tiredness and nausea. Pralsetinib is safe for patients with specific lung cancer types, though it can cause some stomach and blood-related side effects.

Atezolizumab boosts the immune system but can sometimes cause the body to attack its own tissues, leading to inflammation in organs like the lungs. These side effects are uncommon but can be serious. The vemurafenib-cobimetinib combination, approved for skin cancer, has been found safe in long-term studies, though it may cause joint pain and skin issues.

As this is a Phase 2 trial, the treatments have passed initial safety tests in humans. Researchers continue to assess how well patients tolerate them. Based on past research, these treatments are generally considered safe, but more data is being gathered to ensure this for everyone. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for lung cancer because they offer personalized approaches that target specific genetic mutations. Unlike standard treatments, which often involve chemotherapy and radiation, these investigational therapies like divarasib, pralsetinib, and alectinib are tailored to target mutations such as KRAS G12C, RET, and ALK, respectively. This targeted mechanism can potentially improve effectiveness and reduce side effects by precisely attacking cancer cells with these mutations while sparing healthy cells. Additionally, some treatments incorporate innovative combinations, such as atezolizumab with low-dose radiation, which may enhance the immune response against tumors. These advancements could lead to more effective and individualized lung cancer treatment options.

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

Research has shown that combining vemurafenib and cobimetinib for patients with BRAF-mutated lung cancer results in a 70% response rate, with cancer not worsening for about 5.8 months on average. In this trial, participants in the BRAF cohort will receive this combination. Alectinib has proven very effective for ALK-positive lung cancer, controlling the cancer for an average of 25.7 months, and is being studied in the ALK cohort. Entrectinib works well for ROS1 and NTRK mutations, with ROS1-positive patients living an average of 47.8 months, and is included in the ROS1 and NTRK cohorts. Pralsetinib for RET fusion-positive lung cancer shows a high response rate of 68% and an average survival of 23.8 months, and is being tested in the RET cohort. Atezolizumab, combined with a precise form of radiation therapy called SBRT, shows promise in killing more cancer cells and improving treatment for certain lung cancers, and is part of the PD-L1 cohort. Each of these treatments targets specific genetic changes in tumors, offering personalized approaches that have shown promising results in studies. ^{6 7 8 9 10}

Who Is on the Research Team?

Clinical Trials

Principal Investigator

Hoffmann-La Roche

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

Group I: ROS 1 Cohort (Enrolment Closed) Experimental Treatment 3 Interventions

Participants will receive up to 8 weeks of entrectinib neoadjuvant treatment before undergoing surgical resection per SOC. 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. Enrolment Closed.

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

Participants will receive up to 8 weeks of pralsetinib neoadjuvant treatment before undergoing surgical resection per SOC. 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. Cohort closed.

Group III: PD-L1 Cohort (Enrolment Closed) Experimental Treatment 3 Interventions

Participants with positive programmed death-ligand 1 (PD-L1) in ≥1% tumor cells will receive 4 cycles of atezolizumab neoadjuvant treatment. During neoadjuvant Cycle 1 of atezolizumab, participants will also receive low-dose stereotactic body radiation therapy (SBRT) (8 gray \[Gy\] X 3). Adjuvant treatment consists of SOC treatment as determined by the investigator, per National Comprehensive Cancer Network (NCCN) guidelines. Enrolment Closed.

Group IV: NTRK Cohort (Enrolment Closed) Experimental Treatment 3 Interventions

Participants will receive up to 8 weeks of entrectinib neoadjuvant treatment before undergoing surgical resection per SOC. 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. Enrolment Closed.

Group V: KRAS G12C Cohort Experimental Treatment 3 Interventions

Participants will receive up to 8 weeks of divarasib as neoadjuvant treatment before undergoing surgical resection per SOC. PD-L1 negative participants whose tumors have pathological response or lack radiographic progression will be have the option of continuing divarasib alone for up to 3 years or 1-4 cycles of SOC chemotherapy followed by divarasib for 3 years as adjuvant therapy. For participants who test positive PD-L1, they will have the option to receive 1-4 cycles of SOC chemotherapy followed by atezolizumab for up to 16 cycles or SOC alone.

Group VI: BRAF Cohort (No Participants Enrolled, Cohort Closed) Experimental Treatment 4 Interventions

Participants will receive up to 8 weeks of vemurafenib plus cobimetinib neoadjuvant treatment before undergoing surgical resection per SOC. 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. Cohort closed.

Group VII: ALK Cohort (Enrolment Closed) Experimental Treatment 3 Interventions

Participants will receive up to 8 weeks of alectinib neoadjuvant treatment before undergoing surgical resection per standard of care (SOC). 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. Enrolment Closed.

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

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5744742/

Real-world usage and clinical outcomes of alectinib among ... The objective response rate was higher than in clinical trials (67.1% vs 51.3%, respectively) as was the disease control rate (89.9% vs 78.8%, respectively), ...

2. alecensa.com alecensa.com/hcp/metastatic/efficacy/survival-results.html

Survival results for ALECENSA® (alectinib) PFS by IRC: In the ITT population, mPFS was 25.7 months for ALECENSA (95% CI: 19.9, NE) compared with 10.4 months with crizotinib (95% CI: 7.7, ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S0169500225006543

Advanced-stage ALK-positive non–small-cell lung cancer ... Among 382 patients receiving 1L alectinib overall survival (OS) rate was 88.7 % and 73.3 % at 24 and 60 months, respectively. Median progression ...

4. ascopubs.org ascopubs.org/doi/10.1200/JCO.2025.43.16_suppl.8608

Real-world comparative outcomes of alectinib and ... In this real-world study, both alectinib and brigatinib provided favorable survival outcomes in patients with ALK-positive NSCLC.

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5455704/

Three-Year Follow-Up of an Alectinib Phase I/II Study in ALK ... The most common treatment-related adverse event (all grades) was increased blood bilirubin (36.2%). Most cancer symptoms were relieved early, and medication for ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/31706099/

Pooled overall survival and safety data from the pivotal ... Alectinib demonstrated a median OS of 29.1 months (95% CI 21.3-39.0). No new or unexpected safety findings were observed. The most common all-grade AEs included ...

7. alecensa.com alecensa.com/hcp/metastatic/side-effects-and-safety/safety-profile.html

ALECENSA® (alectinib) safety profile Renal impairment occurred in 12% of 533 patients treated with ALECENSA, including Grade ≥3 in 1.7% of patients, of which 0.4% were fatal events · The median time ...

8. alecensa.com alecensa.com/hcp/adjuvant/side-effects/safety-profile.html

The safety observed in the ALINA trial was consistent with ... The safety observed in the ALINA trial was generally consistent with the established ALECENSA safety profile. Most adverse reactions from the trial were mild ...

9. gene.com gene.com/assets/frontend/downloads/media/news-features/fda-approves-new-treatment-option-for-specific-type-of-lung-cancer/Alecensa_Fact_Sheet_03-08-17.pdf

ALECENSA® (alectinib) Fact Sheet ALECENSA is a kinase inhibitor approved for the treatment of people with anaplastic lymphoma kinase (ALK)-positive, metastatic non-small cell lung cancer ...

10. onclive.com onclive.com/view/safety-data-help-affirm-adjuvant-alectinib-as-a-new-soc-in-alk-nsclc

Safety Data Help Affirm Adjuvant Alectinib as a New SOC ... Hidehito Horinouchi, MD, PhD, discusses safety data from the ALINA trial of adjuvant alectinib in ALK-positive non–small cell lung cancer.