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A Phase II Study of Metformin with Pemetrexed/Carboplatin in Patients with Metastatic Non-Squamous Non-Small Cell Lung Cancer
Journal of Thoracic Oncology ; 17(9):S130-S131, 2022.
Artigo em Inglês | EMBASE | ID: covidwho-2031505
ABSTRACT

Introduction:

There is a subset of NSCLC patients ineligible for benefit from TKIs/Immunotherapy (e.g. STK11 mutation conferring resistance to Immunotherapy). Besides, many patients cannot afford these therapies. Metformin has anticancer properties acting both on glycolytic metabolism and tumor microenvironment. In vitro studies suggest synergism between metformin and pemetrexed. STK11 deficient cell lines are more sensitive to metformin. Clinical studies combining metformin with chemotherapy are limited by small sample size. We conducted an exploratory phase-2 clinical trial of metformin with pemetrexed/carboplatin in advanced non-squamous NSCLC.

Methods:

This was a single center, open label, single arm phase 2 clinical trial with a Simon’s two stage design. The null hypothesis was that the combination would not improve the 6-month PFS rate by 15%, from 50%. Treatment-naive, non-diabetic patients aged 18-75 years with NSCLC (adenocarcinoma/not-otherwise-specified) with stage IV disease having ECOG PS 0-2 with unmutated EGFR/ALK and without brain metastasis or with asymptomatic brain metastases were treated with pemetrexed-carboplatin chemotherapy and metformin for six months. The primary outcome was 6-month progression free survival (PFS) rate. Secondary outcomes were safety, overall survival (OS), overall response rate (ORR), proportion of STK 11 mutation and effect of STK 11 mutation on 6-month PFS rate. PFS and OS were estimated using the Kaplan-Meier method. Targeted sequencing was attempted for available tissue specimens.

Results:

The first interim analysis was performed after enrollment of 26 patients for the first stage (before the target accrual of first stage was reached) due to slow accrual, in view of COVID pandemic. The study was terminated after first stage for futility. The median age of patients in the study was 52 years (range, 30 to 68) and 18 patients (69.0%) were males. Half of the patients had ECOG-PS 2. Brain metastases were present in eight (31%) patients and among these four (50%) were symptomatic at presentation. The median follow-up time was 25 months. The median PFS was four months. 6-month PFS rate was 28% (95% CI - 0.12 to 0.46). Of the 25 evaluable patients, five (20%) had a partial response, and eight (32%) had stable disease;13 (52%) of the patients had disease control. The median OS was 16 months. During combined therapy, 14 (54%) and 3 (11%) patients had any grade and grade 3 anemia respectively. One patient had grade 3 neutropenia. Among non-hematological toxicities, gastrointestinal toxicities (nausea, vomiting and diarrhea) were the most common. No grade 4 toxicities were reported. There were no treatment discontinuations, however treatment delay due to grade three toxicities was present in two patients. Dose modification for Metformin was required in four patients. Targeted Sequencing was possible in nine cases. Two of these patients had STK11 mutation and an associated bad outcome (PFS < 2 months).

Conclusions:

We could not demonstrate the benefit of combination of Metformin with pemetrexed-carboplatin in terms of improvement in 6-month PFS rate. The addition of metformin to pemetrexed-carboplatin has an acceptable safety profile. Future trials should test metformin in specific subsets (STK11 mutated) and in combination with immunotherapy and TKIs. Keywords Metformin, NSCLC, STK11
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Texto completo: Disponível Coleções: Bases de dados de organismos internacionais Base de dados: EMBASE Idioma: Inglês Revista: Journal of Thoracic Oncology Ano de publicação: 2022 Tipo de documento: Artigo

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Texto completo: Disponível Coleções: Bases de dados de organismos internacionais Base de dados: EMBASE Idioma: Inglês Revista: Journal of Thoracic Oncology Ano de publicação: 2022 Tipo de documento: Artigo