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Efficacy of nintedanib plus docetaxel in patients with refractory advanced epidermal growth factor receptor mutant lung adenocarcinoma

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Abstract

Background

Anti-angiogenic agents are reported to exert clinical activity in patients with epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC). We evaluated the outcomes of the combination of docetaxel plus nintedanib in refractory NSCLC patients harboring EGFR mutations.

Methods

We retrospectively analyzed 19 patients with advanced EGFR-mutant NSCLC who had progressed to EGFR tyrosine kinase inhibitors (TKI) and platinum-based chemotherapy receiving docetaxel and nintedanib at 14 Spanish institutions from January 2013 to December 2019. Kaplan–Meier and log-rank tests were used to evaluate progression-free survival (PFS) and overall survival (OS).

Results

Median age was 58.9 years (range 42.8–81), 73.7% were female. All patients were Caucasian, and 73.7% were never or light smokers. The baseline Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 0–1 in 94.7% of patients. All patients had adenocarcinoma. Brain and liver metastases were present in 47.4% and 31.6% of patients, respectively. The most common EGFR mutations were exon 19 deletion (52.6%) and exon 21 L858R mutation (36.8%); 47.4% patients presented the EGFR T790M. 94.8% of the patients had received 2–3 previous treatment lines.

Docetaxel was administered at 75 mg/m2/3 weeks to 16 patients, at 60 mg/m2 to 2 patients and at 45 mg/m2 to one patient. Nintedanib was given until disease progression or unacceptable toxicity at 200 mg twice daily except in 2 patients who received 150 mg twice daily and one patient who received 100 mg/12 h.

With a median follow-up of 11.4 months (1–38), the median PFS was 6.1 months [95% confidence interval (CI), 4.9–7.3] and the median OS 10.1 months (95% CI 5.9–14.3). The objective response rate (ORR) was 44.4% (23.7–66.8%) and the disease control rate (DCR) 72.2% (49.4–88.5%). Efficacy tended to be greater in patients with the acquired T790M who had received osimertinib, with a median PFS of 6.3 (95% CI 2.1–10.5) versus (vs.) 4.8 (95% CI 3.5–6.1) and a median OS of 12.3 months (95% CI 8.6–16.0) vs. 6.7 months (95% CI 3.9–9.4), although this tendency was not statistically significant (p = 0.468 and p = 0.159, respectively).

Sixteen patients (84.2%) had a total of 34 adverse events (AEs), with a median of two (0–6) AEs per patient. The most frequent AEs were asthenia (20.6%) and diarrhea (20.6%). One treatment-related death due to portal thrombosis was reported.

Conclusions

Our data indicate that the combination of docetaxel and nintedanib can be considered to be an effective treatment for EGFR TKI-resistant EGFR-mutant NSCLC.

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Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

Authors and Affiliations

  1. Medical Oncology Department, Hospital de La Santa Creu I Sant Pau, Sant Quintí, 89, 08041, Barcelona, Spain

    Mariona Riudavets & Margarita Majem

  2. Medical Oncology Department, Institut Català d’Oncologia (ICO), Hospital Universitari Dr. Josep Trueta, Girona, Spain

    Joaquim Bosch-Barrera

  3. Medical Oncology Department, Hospital Universitario de Torrejón, Madrid, Spain

    Luís Cabezón-Gutiérrez

  4. Medical Oncology Department, Complejo Asistencial Universitario de León, León, Spain

    Pilar Diz Taín

  5. Medical Oncology Department, Institut Català d’Oncologia (ICO), Badalona Applied Research Group in Oncology (B-ARGO Group), Institut Investigació Germans Trias I Pujol (IGTP), Department of Medicine, Universitat Autònoma de Barcelona (UAB), Campus Can Ruti, Badalona, Barcelona, Spain

    Ainhoa Hernández & Teresa Morán

  6. Medical Oncology Department, Hospital Universitario Virgen del Rocío, Sevilla, Spain

    Miriam Alonso

  7. Medical Oncology Department, Consorci Sanitari de Terrassa, Barcelona, Spain

    Remei Blanco

  8. Medical Oncology Department, Hospital General de Elda, Alicante, Spain

    Elisa Gálvez

  9. Medical Oncology Department, Hospital Clínico Universitario de Valencia, Valencia, Spain

    Amelia Insa

  10. Medical Oncology Department, Fundación Hospital Universitario de Alcorcón, Madrid, Spain

    Xabier Mielgo

  11. Medical Oncology Department, Hospital Universitario, 12 de Octubre, Madrid, Spain

    Santiago Ponce

  12. Medical Oncology Department, Hospital de Manacor, Manacor, Spain

    Diana Roa

  13. Medical Oncology Department, Hospital Universitario de la Princesa, Madrid, Spain

    José Miguel Sánchez

Authors
  1. Mariona Riudavets
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Contributions

JB Research grant/Funding (institution), Roche, Pfizer, Boehringer Ingelheim, Consulting and Advisory: Roche, BMS, Astra Zeneca, Novartis, Boehringer Ingelheim. LC Consulting and Advisory: Angelini, Grunenthal, Kyowa Kirin, Mudipharma, Pfizer, Roche, Rovi, Leo Pharma, Merck Serono, Ipsen Pharma, Astra Zeneca. PD Consulting and Advisory: Takeda, Roche, Astra-Zeneca, BMS, MSD, Boehringer Ingelheim. Expert testimony: Takeda, Roche, Astra-Zeneca, BMS, MSD, Boehringer Ingelheim. Lecture speaking: Roche, Astra-Zeneca, BMS, MSD, Boehringer Ingelheim, Amgen, Pfizer. Travel, accommodations, expenses: BMS, MSD, Boehringer Ingelheim, Roche. AH Lecture speaking: Roche, Bristol-Myers Squibb, Consulting and Advisory: Boehringer Ingelheim, Travel. Accomodations, Expenses: Boehringer Ingelheim, Roche,Bristol-Myers Squibb, AstraZeneca. SPo Consulting and Advisory: Roche, MSD, AstraZeneca, Bristol-Myers Squibb, Pharmamar, Boehringer Ingelheim, BMS. Expert testimony: Roche, MSD, Astra Zeneca, Bristol-Myers Squibb, Pharmamar, Boehringer Ingelheim, BMS. Travel, accommodations, expenses: MSD, Roche, BMS, AstraZeneca, Pharmamar. JMS Consulting of Advisory: Astra Zeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer, Roche, Takeda. Travel/Accommodations/Expenses: Boehringer Ingelheim, MSD, Roche. MA Consulting and Advisory: Roche, Astra Zeneca, Bristol-Myers Squibb, Boehringer Ingelheim and Pfizer. RB Speaker honoraria from Roche, Boehringer Ingelheim, Astra Zeneca, MSD, Merck, Pfizer and Sanofi. Consultant or advisory role for Boehringer Ingelheim, Astra Zeneca. AI Consulting and Advisory: Bristol-Myers Squibb, Boehringer Ingelheim, MSD, Pfizer, Roche. Expert testimony: Bristol-Myers Squibb, Boehringer Ingelheim MSD, Pfizer, Roche, AstraZeneca. Travel, accommodations, expenses: Bristol-Myers Squibb, Boehringer Ingelheim, MSD, Pfizer, Roche. EG Consulting and Advisory: Hoffmann-La Roche, Bristol-Myers Squibb, Merck, Boehringer Ingelheim. XM Consulting and Advisory: Boehringer Ingelheim. TM Lecture speaking: Boehringer Ingelheim, Roche, Pfizer, Lilly; Travel, accommodations, Expenses: Boehringer Ingelheim, Roche, Pfizer, Lilly. MM Consulting or Advisory: AstraZeneca, Roche, Bristol-Myers Squibb, Merck Sharp and Dohme, Pfizer, Boehringer Ingelheim, Novartis, Tesaro, Helsinn Therapeutics, Takeda, Sanofi, Amgen; Research Funding: BMS; Travel, accommodations, Expenses: Lilly, AstraZeneca, Roche.

Corresponding author

Correspondence to Margarita Majem.

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Conflict of interest

All the authors contributed equally in the present manuscript. MR no conflict of interest, DR no conflict of interest, RM no conflict of interest.

Ethical approval

This study was approved by Hospital de la Santa Creu i Sant Pau Ethics Committee ( IIBSP-CAP-2021-83).

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For this type of study, formal consent is not required.

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Riudavets, M., Bosch-Barrera, J., Cabezón-Gutiérrez, L. et al. Efficacy of nintedanib plus docetaxel in patients with refractory advanced epidermal growth factor receptor mutant lung adenocarcinoma. Clin Transl Oncol 23, 2560–2567 (2021). https://doi.org/10.1007/s12094-021-02661-2

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