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A phase II study of afatinib in combination with pemetrexed and carboplatin in Japanese patients with EGFR mutation positive (mEGFR+) non-squamous (SQ), advanced non-small cell lung cancer (NSCLC) refractory to first-line osimertinib treatment. (NEJ025B)

NEJ025B (NEJ025B)

36

The mean age was 70 years, 60% were women, and 54.3% were nonsmokers; 15 (42.9%) were PS0 and 20 (57.1%) were PS1. The histologic type was adenocarcinoma in 94.3%, and the genetic types were exon 19 deletion in 42.9% and L858R mutation in 57.1%. Clinical stage was stage IVA in 11 cases (31.4%), stage IVB in 19 cases (54.3%), and postoperative recurrence in 5 cases (14.3%). There were no stage III cases. Asymptomatic brain metastases were present in 13 cases (37.1%)

Between June 7, 2020 and January 19, 2022, 36 patients were enrolled; one patient was excluded due to the discovery of a cancer other than lung cancer, and the other 35 patients were analyzed for efficacy.

Anemia (97.2%), lymphopenia (86.1%) and thrombocytopenia (77.8%) were frequently seen in all grades. Diarrhea (52.8%), anorexia (47.2%), fatigue (36.1%), and paronychia (36.1%) were the next most frequent adverse events. These adverse events were predictable and manageable. Interstitial pneumonia occurred in three patients (8.3%), one of whom died. Sepsis resulted in the death of one patient (3%).

The 6M-PFSR as the primary endpoint was 57.1% (95%Cl 39.3-71.5) . The study met its primary endpoint with a confidence interval above the 35% threshold. The median PFS was 8.2 months (95%Cl 4.8~10.4). The median DOR was 5.6 months (95%Cl 1.9~11.7). The median overall survival was 22.5 months (95% Cl 17.2~32.4). In terms of mutation type, the median PFS was 9.6 months (95% Cl 5.6~11.7) for patients with exon 19 deletion mutation lung cancer and 5.2 months (95% Cl 3.9~13.0) for patients with L858R mutation lung cancer. Patients with exon 19 deletion mutated tumor tended to have longer PFS than patients with L858R mutated tumor, but it was not statistically significant. The median PFS for patients who responded to osimertinib pretreatment (CR, PR: n=29) was 8.5 months (95%Cl 4.4~12.0), and for non-responders (SD, PD, NE: n=6) was 5.8 months (95%Cl 3.5~NE). Of the 35 patients, 18 (51.4%) were PR, 13 (37.1%) SD, 3 (8.6%) PD, and 1 (2.9%) NE. Consequently, ORR was 51.4% (95% Cl 34.0~68.6), and DCR was 88.6% (95% Cl 73.3~96.8). There was no difference in ORR between exon 19 deletion and L858R mutation (46.7%, 95% CI 21.3~73.4 vs 55%, 95% CI 31.5~76.9, respectively). In plasma NGS analysis, clearance of EGFR mutations during treatment was a key predictive factor. patients without EGFR mutation clearance had shorter PFS and OS compared to those with clearance (PFS: 5.7 vs. 12.0 months; OS: 15.7 vs. 34.4 months). Efficacy was observed even in patients with p53 mutations, a known resistance factor. MET gene amplification was detected in 4 patients upon resistance.

Afatinib combined with platinum-based chemotherapy demonstrated satisfactory efficacy and manageable toxicity in pts with tumors refractory to osimertinib. EGFR mutation clearance during treatment was predictive of therapeutic outcomes. This regimen may be a promising second-line option after osimertinib failure.

Sept. 24, 2025

Aug. 20, 2025

https://pubmed.ncbi.nlm.nih.gov/40957291/

No

https://jrct.mhlw.go.jp/latest-detail/jRCTs021200005

Maemondo Makoto

Jichi Medical University Hospital

3311-1 Yakushiji, Shimotsuke-shi, Tochigi-ken

maemondo@gmail.com

Sato Haruna

Jichi Medical University Hospital

3311-1 Yakushiji, Shimotsuke-shi, Tochigi-ken

+81-285-58-7350

r1126hk@jichi.ac.jp

Complete

May. 01, 2020

Interventional

single arm study

open(masking not used)

uncontrolled control

single assignment

treatment purpose

1)A histologically or cytologically confirmed diagnosis of non-small-cell lung cancer other than squamous cell carcinoma.
2)Have clinical stage IIIB, IIIC, IVA, IVB or postoperative recurrent non-small-cell lung cancer that cannot be treated with radical radiotherapy and surgery.
3)An observed Exon 19 deletion mutation or Exon 21 L858R mutation in tumor tissue or tumor cells before osimertinib treatment.
4)They have 1 or more measurable lesions based on the criteria in Response Evaluation Criteria in Solid Tumors (RECIST)Version 1.1 after failure of osimertinib.
5)Confirmed PD of previous osimertinib treatment as a first-line treatment. Regardless of treatment duration of osimertinib.
6)Recovering from adverse effect until grade1 or less.
7) Be a case where chemotherapy or immunotherapy has not yet been carried out, excluding neoadjuvant and adjuvant chemotherapy 6 months before enrollment and pleurodesis a week before enrollment.
8)Be aged 20 years or over at the time of consent acquisition.
9)Have an ECOG performance status (PS) of 0 to 1.
10)Main organ functions must meet the following criteria within two weeks prior to enrollment. If there are multiple test results within this period, then the most recent test prior to enrollment will be adopted.
1) Neutrophil count 1,500/mm3 or above
2)Lymphocyte count 500/mm3 or above
3)Hemoglobin 9.0 g/dL or above
4)Platelet count 10.0 x104/mm3 or above
5)AST 2.5 times the upper limit of the site's standard values or below
6)ALT 2.5 times the upper limit of the site's standard values or below
7)Total bilirubin 1.5 times the upper limit of the site's standard values or below
8)Serum creatinine 1.5 times the upper limit of the site's standard values or below
9)Creatinine Clearance 45 mL/min or above
10) PaO2 (room air) 70 Torr or above, or SpO2 93% or above
11) The details of this study were sufficiently explained to the patient and written consent was obtained from the patient them self.

1)Have active interstitial lung disease, or a history of drug-induced pneumonitis, radiation pneumonitis needing steroid treatment.
2)The patient has brain metastasis that requires anti-edema drugs such as steroids for symptomatic brain metastases or symptom management and meningitis carcinomatosa.
*Asymptomatic brain metastasis is not excluded.
3) Have a history of irradiation directed at the lesions in the lung field or other target lesion.
*Enrollment is permitted in cases which have had palliative irradiation for bone lesions in the chest, if at the time of enrollment 2 weeks or more have elapsed since the final day of irradiation.
4) Currently have serious complications including uncontrolled lung, liver, and renal disease.
5)Have heart disease that could be clinically problematic (such as uncontrollable hypertension, unstable angina, congestive heart failure, advanced arrhythmia requiring treatment with medication, or a history of myocardial Infarction within 12 months prior to enrollment).
* treatment of hypertension is eligible.
6) Currently have or have a history of the following serious complications:
-Also have superior vena cava syndrome.
-Have spinal cord compression.
-Also have symptomatic cerebrovascular disease or have a history of cerebrovascular disease within 3 months before enrollment.
-Have unhealed bone fractures (excluding the like associated with osteoporosis) or advanced wounds
-Have infectious diseases requiring systemic administration of antibiotics, antifungal agents or antiviral agents.
7) Have uncontrolled gastrointestinal disturbances affecting intestinal absorption of afatinib (such as Crohn's disease, ulcerative colitis, chronic diarrhea, and malabsorption).
8)Have an active hepatitis being positive for HBV DNA* and HIV infection.
*Measure HBV DNA if the patient is positive for HBs antigens, HBs antibodies or HBc antibodies
9) Women who are currently pregnant or breastfeeding. Or women who are capable of becoming pregnant. Men who want to partner's pregnancy.
10) Be undergoing systemic administration of steroids for 4 weeks or more (however, enrollment is permitted for steroids in terms of within prednisolone 10 mg/day).
11)Have pleural effusion, ascites or pericardial effusion that require drainage (enrollment is permitted if the symptoms stabilize a week after drainage).
12) Have contraindication to afatinib, carboplatin, or pemetrexed.
13) The patient has complications with double cancers that have a disease-free period of less than 5 years (enrollment is permitted if intraepithelial carcinoma and intramucosal carcinoma lesions have been judged as cured from localized treatment regardless of the disease-free period).
14) Have significant neuropathy or psychosis (includes dementia and epileptic seizures).
15) Surgery is planning during study period.
16) Have serious hypersensitivity to afatinib, carboplatin, or pemetrexed.
17) Individuals who are deemed to be unsuitable for participation in this study by the principal investigator or sub-investigators for any other reason.

Both

Non-sequamous non-small cell lung cancer

Induction therapy: carboplatin AUC 5 day1+ pemetrexed 500 mg/m2 day1 q3w 4 cycles and afatinib 20 mg/body every day.
Maintenance therapy: pemetrexed 500 mg/m2 day1 q3w and afatinib 20 mg/body every day until PD.

Progression-Free Survival Rate at 6 months

Overall Survival,Progression-Free Survival,Objective Response Rate,Duration Of Response,Safety,Difference of efficacy of study treatment among EGFR mutation types,Association with response of prior osimertinib treatment,Biomarker analyses

+81-19-651-5111

April. 06, 2020

none