ORIENT-31 plus targeted SBRT for EGFR‑mutant metastatic lung cancer after third‑generation EGFR‑TKI

ORIENT-31 Regimen (Sintilimab Plus Bevacizumab Plus Platinum-doublet Chemotherapy) in Combination With Stereotactic Radiotherapy in EGFR-mutant Metastatic Non-small Cell Lung Cancer After First-line Third-generation EGFR Tyrosine Kinase Inhibitors (ORBIT Study)

This study will test whether adding targeted stereotactic radiotherapy (SBRT) to the ORIENT-31 drug combination helps people with EGFR‑mutant metastatic non‑small cell lung cancer whose disease progressed after first‑line third‑generation EGFR‑TKIs.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 53 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Fudan University (Academic / other)
• Drugs / interventions: chemotherapy, immunotherapy, radiation, Sintilimab, bevacizumab
• Locations: 1 site (Shanghai, Shanghai Municipality)
• Trial ID: NCT06775743 on ClinicalTrials.gov

What this trial studies

This is a prospective phase 2 study enrolling patients with stage IV NSCLC harboring common EGFR sensitizing mutations (L858R or exon 19 deletion) who progressed on first‑line third‑generation EGFR‑TKIs. Participants receive the ORIENT‑31 regimen (sintilimab + bevacizumab + platinum chemotherapy + pemetrexed) with response evaluated every two treatment courses. Based on those evaluations, personalized stereotactic body radiotherapy (SBRT) is given to selected lesions to try to improve local control. The primary focus is on safety and preliminary signs of clinical benefit in this EGFR‑resistant population.

Who should consider this trial

Good fit: Ideal candidates are adults with stage IV EGFR‑mutant NSCLC (L858R or exon 19 deletion) who progressed on first‑line third‑generation EGFR‑TKIs, have ECOG performance status 0–1, measurable disease, adequate organ function, and any brain metastases must be asymptomatic and stable without steroids.

Not a fit: Patients with poor performance status (ECOG ≥2), significant organ dysfunction, symptomatic or unstable brain metastases, or tumors without EGFR‑sensitizing mutations are unlikely to benefit from this approach.

Why it matters

Potential benefit: If successful, combining SBRT with the ORIENT‑31 regimen could improve local tumor control and extend the time before further disease progression for patients who have failed third‑generation EGFR‑TKIs.

How similar studies have performed: Combinations of PD‑1/PD‑L1 inhibitors with anti‑VEGF therapy and chemotherapy have shown activity in lung cancer, but adding SBRT in the specific setting of post‑third‑generation EGFR‑TKI resistance is a relatively novel approach.

Eligibility criteria

Inclusion Criteria:

* ECOG performance status score of 0-1;
* Histologically or cytologically confirmed stage IV primary non-small cell lung cancer;
* EGFR-sensitive mutations (L858R, 19del);
* Resistance to first-line treatment with third-generation EGFR-TKIs;
* At least one measurable lesion;
* Patients with brain metastases may be included, but they must be asymptomatic neurologically and have stable lesions without the need for systemic corticosteroid treatment;
* Men and women of reproductive age agree to contraception during the trial (surgical sterilization or oral contraceptives/intrauterine device + condoms);
* Life expectancy ≥ 3 months;
* Within one week before enrollment, organ function levels must meet the following criteria:

  1. Bone marrow function: Hemoglobin ≥ 80 g/L, white blood cell count ≥ 4.0 × 10\^9/L or neutrophil count ≥ 1.5 × 10\^9/L, platelet count ≥ 100 × 10\^9/L;
  2. Liver: Serum total bilirubin level ≤ 1.5 times the upper limit of normal, and when serum total bilirubin level \> 1.5 times the upper limit of normal, direct bilirubin level must be ≤ the upper limit of normal, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 times the upper limit of normal;
  3. Kidney: Serum creatinine level \< 1.5 times the upper limit of normal or creatinine clearance rate ≥ 50 ml/min, blood urea nitrogen ≤ 200 mg/L; serum albumin ≥ 30 g/L;
* Patients must have the capacity to understand and voluntarily sign the informed consent form.

Exclusion Criteria:

* Patients with severe autoimmune diseases: active inflammatory bowel disease (including Crohn's disease, ulcerative colitis), rheumatoid arthritis, scleroderma, systemic lupus erythematosus, autoimmune vasculitis (such as Wegener's granulomatosis), etc.
* Symptomatic interstitial lung disease or active infectious/non-infectious pneumonia.
* Patients with risk factors for intestinal perforation: active diverticulitis, intra-abdominal abscess, gastrointestinal (GI) obstruction, abdominal cancer, or other known risk factors for intestinal perforation.
* History of other malignant tumors.
* Patients with active infections, heart failure, myocardial infarction within the past 6 months, unstable angina, or unstable arrhythmias.
* Physical examination or clinical laboratory findings that the investigator believes may interfere with the results or increase the risk of treatment complications, or other uncontrollable diseases.
* Patients whom the investigator believes currently have lesions requiring palliative radiation therapy.
* Mixed with small cell lung cancer components.
* Nursing or pregnant women.
* Congenital or acquired immunodeficiency diseases including human immunodeficiency virus (HIV), or history of organ transplantation or allogeneic stem cell transplantation.
* Known hepatitis B virus (HBV), hepatitis C virus (HCV), or active tuberculosis infection.
* Patients who have received cancer vaccines or received other vaccines within 4 weeks before starting treatment (Note: Seasonal influenza vaccines are often inactivated vaccines and are allowed, while intranasal preparations are usually live attenuated vaccines and are not allowed).
* Patients who are concurrently using other immunotherapies, chemotherapy drugs, drugs from other clinical trials, or require long-term corticosteroid treatment are not eligible for enrollment.
* Patients with psychiatric disorders, substance abuse, or social issues that affect compliance are not eligible for enrollment after physician review.
* Patients who are allergic to or contraindicated for PD-1 monoclonal antibodies, VEGF monoclonal antibodies, or chemotherapy drugs.

Withdrawl criteria:

* Incorrectly enrolled participants. Those who have not yet received treatment in this study should be immediately withdrawn, and their information will not be included in the study analysis. If treatment has already begun, the investigator should assess the participant's benefit-risk profile and then decide whether to withdraw. If withdrawal is necessary, the participant should exit the study after completing treatment and follow-up and will not be included in the efficacy analysis of this study, but must be included in the safety analysis.
* Participants who experience the following during the pre-treatment evaluation phase: new systemic diseases or worsening of existing systemic diseases that meet exclusion criteria; voluntary withdrawal, loss to follow-up, or death; poor compliance.
* Participants whom the investigator deems necessary to exclude. The investigator must report the reason for exclusion to the principal investigator and obtain consent. Those who have not yet received treatment in this study should be immediately withdrawn, and their information will not be included in the study analysis. If treatment has already begun, the participant should exit the study after completing treatment and follow-up and will not be included in the efficacy analysis of this study, but must be included in the safety analysis.
* Participants may request to withdraw from the clinical trial at any time during the trial process.
* Participants who experience serious adverse events during the trial, and whom the investigator deems should stop participating in the trial.
* Participants whose condition worsens during the trial, potentially threatening their life, or who develop other conditions that affect trial observations.
* Participants who are lost to follow-up or die during the treatment phase.
* Participants who use chemotherapy, traditional Chinese medicine, other immunotherapy drugs, radiotherapy sensitizers, or other agents that affect efficacy and toxicity evaluation during the trial period.
* Participants in whom serious deviations occur during the implementation of the clinical trial protocol, making it difficult to evaluate the drug's effect; those with poor compliance.

Exit criteria:

* Wrong enrollees who did not meet the inclusion criteria;
* Serious protocol violations.

Where this trial is running

Shanghai, Shanghai Municipality

• Fudan University Shanghai Cancer Center — Shanghai, Shanghai Municipality, China (Recruiting)

Study contacts

• Study coordinator: Zhengfei Zhu, PhD

Conditions NSCLC; EGFR Mutation Positive Advanced Non Small Cell Lung Cancer