JS111 in Patients With Advanced NSCLC Harboring EGFR Mutations

A Phase I/II Clinical Study to Evaluate JS111 Capsules in Patients With Locally Advanced, Metastatic, or Recurrent Non-Small Cell Lung Cancer (NSCLC) Harboring Epidermal Growth Factor Receptor (EGFR) Mutations.

To evaluate the safety, tolerability, and preliminary efficacy of JS111 capsules in patients with locally advanced, metastatic, or recurrent NSCLC harboring EGFR mutations;to determine the recommended Phase II dose (RP2D).

This is a Phase II clinical study evaluating JS111 capsules (AP-L1898) as monotherapy in patients with advanced NSCLC harboring EGFR mutations.Approximately 3 to 42 treatment-naïve patients with EGFR mutation-positive locally advanced, metastatic, or recurrent NSCLC will be enrolled.Based on prior safety, PK, and efficacy data, two dose levels-160 mg QD and 240 mg QD-will be tested to assess safety, tolerability, PK, and preliminary efficacy, and to determine the recommended Phase II dose (RP2D), as referenced in Section 4.3.

The study includes two parts:

Part 1:

Each dose group will enroll 3-12 subjects who will receive oral JS111 capsules daily until meeting treatment discontinuation criteria. Once all subjects complete at least the Day 21 observation following the first dose 21 days of treatment , the Safety Monitoring Committee (SMC) will review the data to decide whether to:

1. Select RP2D for further enrollment;
2. Continue enrollment for further evaluation;
3. Explore other dose levels;
4. Amend or terminate the study if needed. Subjects who receive <80% of planned doses or discontinue for non-drug-related reasons during the 21-day period will be replaced. Mutation subtypes (exon 19 deletion or exon 21 L858R) will be evenly assigned across dose groups, starting from the lower dose.

Part 2:

Subjects will be enrolled into the RP2D cohort until ~30 patients have been treated with the dose. Subjects from the other group may continue on the same dose or switch to RP2D as appropriate. JS111 will be taken once daily in 21-day cycles to further assess safety, PK, and preliminary efficacy.

Inclusion Criteria:

1. Male or female subjects aged ≥18 years at the time of signing informed consent.
2. Histologically or cytologically confirmed locally advanced, metastatic, or recurrent NSCLC that is unresectable and unsuitable for curative chemoradiotherapy.
3. No prior systemic anti-tumor therapy for locally advanced or metastatic NSCLC.
4. Confirmed presence of EGFR-sensitizing mutations (exon 19 deletion or L858R mutation), either alone or co-occurring with other EGFR mutations (including T790M-positive cases). Local laboratory results are acceptable if the test is well-validated, qualified through external quality assessment or molecular diagnostics certification, or approved by NMPA.
5. At least one measurable lesion according to RECIST v1.1.
6. ECOG performance status of 0 or 1.
7. Life expectancy of ≥12 weeks.
8. Adequate function of key organs.
9. Women of childbearing potential (WOCBP) with non-sterilized male partners must have a negative serum pregnancy test within 7 days prior to first dosing and agree to use effective contraception from informed consent signing until 2 months after the last dose.
10. Non-sterilized male subjects with female partners of childbearing potential must agree to use effective contraception (as described in Section 10.3.2) from informed consent signing until 4 months after the last dose and must refrain from sperm donation during this period.
11. Willingness to participate and signed informed consent provided by the subject.

Exclusion Criteria:

1. Presence of any of the following disease conditions.

   a. Histologically or cytologically confirmed small cell lung cancer (SCLC) components, large cell neuroendocrine carcinoma, or sarcomatoid features；b. Conditions that may affect oral drug absorption, distribution, metabolism, or excretion (e.g., inability to swallow, severe vomiting, uncontrolled diarrhea, major GI surgery, Crohn's disease, ulcerative colitis)；c. Known leptomeningeal metastasis；d. Symptomatic brain metastases；e. Uncontrolled pleural effusion, pericardial effusion, or ascites requiring frequent drainage (e.g., ≥ once per month)；f. Untreated or symptomatic spinal cord compression; or previously treated spinal cord compression not stable for at least 4 weeks before enrollment；

2. Prior or concurrent treatments.

   a. Any previous treatment with EGFR-TKIs;b. Use of strong CYP3A inhibitors/inducers within 14 days before the first dose or requirement for such treatment during the study;c. Ongoing treatment with drugs known to prolong QT interval or cause Torsades de Pointes;d. Receipt of any investigational drug within 4 weeks or 5 half-lives (whichever is shorter) before first dosing;e. Concurrent participation in another clinical study, unless it is non-interventional or in follow-up phase;f. Major surgery (e.g., craniotomy, thoracotomy, laparotomy) within 4 weeks before first study drug administration;g. Local radiotherapy within 14 days before the first dose (e.g., palliative radiotherapy for bone metastases);

3. Unresolved toxicities from prior anti-tumor therapy not recovered to ≤ Grade 1 per CTCAE, except for alopecia, Grade 2 peripheral neuropathy, or Grade 2 hypothyroidism judged to be non-risk by the investigator.

4. Known hypersensitivity to study drug or its excipients.

5. Cardiac abnormalities, including.

   a. QTcF ≥450 ms for males or ≥470 ms for females (mean of 3 ECGs during screening);b. Clinically significant arrhythmias (e.g., complete left bundle branch block, 3rd-degree AV block, PR interval >250 ms);c. Risk factors for Torsades de Pointes (e.g., hypokalemia, family history of long QT syndrome or inherited arrhythmias); d. Left ventricular ejection fraction (LVEF) <50%;

6. History or suspected diagnosis of interstitial lung disease, drug-induced pneumonitis, idiopathic pulmonary fibrosis, or other significant pulmonary diseases (except for ≤ Grade 1 radiation pneumonitis).

7. Serious infection (CTCAE > Grade 2) within 4 weeks prior to first dosing, such as pneumonia requiring hospitalization. Active pulmonary inflammation on baseline imaging or infection symptoms requiring antibiotics within 2 weeks prior to dosing (excluding prophylactic use).

8. History of immunodeficiency, including HIV positivity, congenital or acquired immunodeficiency disorders, or history of organ/allogeneic bone marrow transplantation or autologous stem cell transplantation.

9. Active tuberculosis or history of active TB within 1 year prior to enrollment; or untreated TB if diagnosed over 1 year ago.

10. Active hepatitis B (HBsAg positive and HBV DNA ≥500 U/mL) or hepatitis C (anti-HCV positive and HCV RNA above the detection limit).

11. History of other malignancies unless low-risk (5-year survival >90%) and adequately treated, e.g., basal/squamous cell carcinoma of the skin, in situ cervical or breast cancer, localized prostate cancer, or papillary thyroid carcinoma.

12. Pregnant or breastfeeding women, or those planning to become pregnant during the study.

13. Uncontrolled comorbid conditions.

14. Any serious or uncontrolled ocular disease.

15. Any other condition judged by the investigator as potentially leading to early withdrawal from the study.