A Phase II Clinical Trial of Anlotinib in Combination With Platinum-based Chemotherapy in Patients With SMARCA4-Deficient, Locally Advanced or Metastatic Lung Cancer.
Overview
- Phase
- Phase 2
- Status
- Not yet recruiting
- Sponsor
- Zhijie Wang
- Enrollment
- 28
- Locations
- 1
- Primary Endpoint
- Progression-Free Survival (PFS)
Overview
Brief Summary
The goal of this clinical trial is to evaluate the efficacy and safety of combining Anlotinib with platinum-based chemotherapy for treating locally advanced or advanced lung cancer in patients whose tumors are characterized by SMARCA4 deficiency, as evidenced by the loss of BRG1 protein via immunohistochemistry (IHC). It will also learn about the safety of this combination treatment.
The main questions it aims to answer are:
- How long can this treatment delay the worsening of the cancer (Progression-Free Survival, PFS)?
- What side effects or medical problems do participants have when taking this combination? This is a single-arm study, meaning all participants will receive the same investigational combination therapy. Researchers will monitor how well the cancer responds and compare the results to historical data from similar patients who received other treatments.
Participants will:
- Receive treatment in 21-day cycles: take Anlotinib pills on days 1-14 of each cycle and receive platinum-based chemotherapy by intravenous infusion on day 1 (or days 1 and 8).
- Undergo regular clinic visits for imaging scans (like CT scans), blood tests, and physical examinations to check the cancer's status and their overall health.
- Complete questionnaires about their quality of life.
- Provide tumor tissue and blood samples for exploratory research to understand which patients might benefit most from this treatment.
Treatment will continue until the cancer worsens, side effects become intolerable, the participant decides to withdraw, or the study ends.
Detailed Description
SMARCA4-deficient non-small cell lung cancer (NSCLC) is a distinct and highly aggressive molecular subtype, characterized by inactivating mutations or loss of the SMARCA4 gene, which encodes the BRG1 protein. It constitutes approximately 5-10% of all NSCLC cases. Patients typically present with advanced-stage disease at diagnosis and exhibit a notoriously poor prognosis, with historical median overall survival (mOS) often ranging from 4 to 7 months. Current standard first-line therapies, including immune checkpoint inhibitor (ICI) combinations, have shown limited and inconsistent efficacy in this specific population, creating a significant unmet medical need.
Therapeutic options for SMARCA4-deficient NSCLC remain an area of active investigation. While platinum-doublet chemotherapy forms the backbone of treatment, the added benefit of ICIs is ambiguous. Large retrospective analyses suggest that tumors harboring SMARCA4 alterations may derive less benefit from frontline chemoimmunotherapy compared to wild-type tumors, highlighting the intrinsic resistance mechanisms and unique tumor microenvironment of this subtype. Therefore, exploring novel combination strategies beyond conventional immunotherapy is critical.
Anlotinib is an orally administered, multi-targeted tyrosine kinase inhibitor that potently inhibits key angiogenesis pathways (VEGFR, PDGFR, FGFR) as well as tumor proliferation pathways (c-Kit, RET). It is approved in China for later-line treatment of advanced NSCLC. Beyond its anti-angiogenic effects, preclinical and clinical evidence suggests that Anlotinib may modulate the tumor immune microenvironment and synergize with chemotherapy to enhance anti-tumor activity. The rationale for combining Anlotinib with platinum-based chemotherapy in SMARCA4-deficient NSCLC is multi-faceted: 1) to provide a robust cytotoxic backbone; 2) to simultaneously inhibit tumor angiogenesis, a potential driver of aggressiveness; and 3) to potentially re-sensitize or circumvent the relative immunotherapy resistance observed in this subtype.
To date, no prospective clinical trial data exist on the use of Anlotinib combined with platinum-based chemotherapy as a first-line treatment for SMARCA4-deficient NSCLC. This phase II, single-arm, open-label study is designed to prospectively evaluate the efficacy and safety of this novel combination regimen in patients with locally advanced or metastatic SMARCA4-deficient NSCLC, confirmed by immunohistochemical loss of BRG1 protein.
The primary objective is to assess progression-free survival (PFS). Secondary objectives include objective response rate (ORR), disease control rate (DCR), duration of response (DoR), overall survival (OS), safety profile, and health-related quality of life (HRQoL). Exploratory biomarker analyses on tumor tissue and blood samples will investigate molecular features of the tumor and its microenvironment to identify potential predictors of response and resistance.
This study aims to generate the first prospective evidence for a targeted-chemotherapy combination in this challenging disease, potentially offering a new and effective first-line treatment strategy for patients with SMARCA4-deficient NSCLC.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Patients must meet ALL the following criteria to be eligible for trial participation:
- •Voluntary participation and provision of written informed consent.
- •Age ≥ 18 years.
- •Life expectancy ≥ 3 months.
- •Diagnosed with unresectable, locally advanced (Stage IIIB) or metastatic (Stage IV) lung cancer not amenable to curative radiotherapy.
- •Tumor confirmed by immunohistochemistry (IHC) to be deficient in the BRG1 protein (encoded by the SMARCA4 gene).
- •No prior systemic anti-cancer therapy.
- •Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or
- •Willing and able to provide archival or fresh tumor tissue samples from primary or metastatic sites for biomarker analysis. Enrollment may be considered after investigator assessment if tissue is unavailable, provided all other criteria are met.
- •At least one measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.
Exclusion Criteria
- •Patients meeting any of the following criteria will be excluded from the trial:
- •Pathological diagnosis containing a small cell carcinoma component.
- •Symptomatic brain metastases.
- •Leptomeningeal carcinomatosis.
- •Failure to recover from acute toxicities of prior anti-cancer therapy to ≤ Grade 1 per NCI CTCAE v5.0 or to baseline levels specified in the inclusion criteria (excluding alopecia or fatigue) within 4 weeks prior to the first dose.
- •Conditions that compromise intravenous access or oral drug administration (e.g., inability to swallow, chronic diarrhea, intestinal obstruction); OR unwillingness or inability to undergo a repeat biopsy or provide sufficient tissue samples for comprehensive analysis (whole-exome sequencing, transcriptome sequencing, multiplex fluorescence immunohistochemistry).
- •Failure to recover from adverse reactions of prior therapies to ≤ Grade 1 per CTCAE v5.0, except for toxicities deemed by the investigator to pose no safety risk (e.g., Grade 2 alopecia, Grade 2 peripheral neuropathy, Grade 2 anemia, non-clinically significant and asymptomatic laboratory abnormalities, or stable hypothyroidism on hormone replacement therapy).
- •Major surgical procedure, significant traumatic injury within 4 weeks prior to the first dose, or anticipated need for major surgery during the study treatment period (unless specified in the protocol); OR presence of non-healing wounds or fractures. (Major surgery is defined as Grade 3 or higher according to the National Surgery Classification Catalog 2022 edition).
- •Any arterial or venous thromboembolic event (e.g., cerebrovascular accident, transient ischemic attack, deep vein thrombosis, pulmonary embolism) within 6 months prior to the first dose; OR any bleeding or hemorrhagic event ≥ Grade 3 per CTCAE v5.0 within 4 weeks prior to the first dose.
- •Poorly controlled active viral hepatitis. Eligible subjects meeting the following criteria may be screened:
Arms & Interventions
combined treatment group
This study evaluates a first-line treatment for locally advanced or metastatic SMARCA4-deficient lung cancer, combining Anlotinib-an oral multi-target tyrosine kinase inhibitor that primarily inhibits tumor angiogenesis-with platinum-based chemotherapy. The rationale for this combination is to integrate potent anti-angiogenic therapy with standard cytotoxic chemotherapy, aiming to address the limited efficacy of current standard therapies in this aggressive molecular subset.
Patients receive the combination of Anlotinib and platinum-doublet chemotherapy for 4-6 induction cycles, followed by Anlotinib monotherapy as maintenance treatment until disease progression or unacceptable toxicity. This design aims to maximize disease control while balancing long-term treatment tolerability.
No prior prospective clinical studies have specifically evaluated this regimen in patients with SMARCA4-deficient NSCLC confirmed by BRG1 protein loss.
Intervention: Anlotinib, nab-paclitaxel, carboplatin (Drug)
Outcomes
Primary Outcomes
Progression-Free Survival (PFS)
Time Frame: From enrollment to the end of monitoring at 2 years.
PFS is defined as the time from the first dose of study treatment to the first documentation of disease progression according to RECIST v1.1 (as assessed by investigators) or death from any cause, whichever occurs first. Subjects who are alive without progression at the time of analysis will be censored at the date of the last tumor assessment.
Secondary Outcomes
- Disease Control Rate (DCR)(From enrollment to the end of monitoring at 2 years.)
- Objective Response Rate (ORR)(From enrollment to the end of monitoring at 2 years.)
- Overall Survival (OS)(From enrollment to the end of monitoring at 2 years.)
- Duration of Response (DoR)(From enrollment to the end of monitoring at 2 years.)
- The incidence of adverse events(From enrollment to the end of monitoring at 2 years)
- Health-Related Quality of Life (HRQoL)(From enrollment to the end of monitoring at 2 years)
Investigators
Zhijie Wang
Professor
Cancer Institute and Hospital, Chinese Academy of Medical Sciences