Real-world global data on targeting epidermal growth factor receptor mutations in stage III non-small-cell lung cancer: the results of the KINDLE study

Abdul Rahman Jazieh, Huseyin Cem Onal, Daniel Shao-Weng Tan, Ross A Soo, Kumar Prabhash, Amit Kumar, Reto Huggenberger, Byoung Chul Cho, Abdul Rahman Jazieh, Huseyin Cem Onal, Daniel Shao-Weng Tan, Ross A Soo, Kumar Prabhash, Amit Kumar, Reto Huggenberger, Byoung Chul Cho

Abstract

Background: Tyrosine kinase inhibitors (TKIs) are the standard of care for resectable and metastatic non-small-cell lung cancer (NSCLC) harbouring epidermal growth factor receptor (EGFR) mutations (EGFRm). We describe the real-world practice of EGFRm testing, prevalence, treatment and outcomes in EGFRm stage III NSCLC from a multi-country, observational study.

Methods: The KINDLE study retrospectively captured diagnostic information, treatments and survival outcomes in patients with stage III NSCLC from January 2013 to December 2017. Baseline characteristics and treatments were described and real-world outcomes from initial therapy were analysed using Kaplan-Meier methods.

Results: A total of 3151 patients were enrolled across three regions: Asia (n = 1874), Middle East and North Africa (MENA) (n = 1046) and Latin America (LA) (n = 231). Of these, 1114 patients (35%) were tested for EGFRm (46% in Asia, 17% in MENA and 32% in LA) and EGFRm was detected in 32% of tested patients (34.3% in Asia, 20.0% in MENA and 28.4% in LA). In a multi-variate analysis, overall EGFRm patients treated with EGFR-TKI monotherapy as initial treatment, without any irradiation, had twice the risk of dying (hazard ratio: 1.983, 95% confidence interval: 1.079-3.643; p = 0.027) versus any other treatment. Finally, unresectable patients with EGFRm NSCLC who received concurrent chemoradiotherapy (cCRT) as initial therapy had longer overall survival (OS) compared with their counterparts who only received TKI monotherapy without any irradiation (48 months versus 24 months; p < 0.001).

Conclusion: The KINDLE study showed that a minority of stage III NSCLC patients were tested for EGFRm. Patients with EGFRm with unresectable NSCLC had similar outcomes from cCRT as initial therapy compared with EGFR wild type with a trend in OS favouring the EGFRm group. Outcomes with EGFR-TKI monotherapy as initial therapy, without any irradiation, were worse. The ongoing LAURA study (NCT03521154) will help define the role of EGFR-TKIs in EGFRm stage III NSCLC treated with cCRT.

Trial registration: NCT03725475.

Keywords: epidermal growth factor receptor; non-small-cell lung cancer; stage III; tyrosine kinase inhibitors; unresectable.

Conflict of interest statement

Competing interests: Disclosure: ARJ reports receiving research support from AstraZeneca, Merck Sharp & Dohme, and Pfizer and travel support from Bristol-Myers Squibb and AstraZeneca. DSWT reports having advisory role and serving as consultant for Novartis, Bayer, Boehringer Ingelheim, Celgene, AstraZeneca, Eli Lilly, and Loxo Oncology; receiving travel support and honorarium from Merck, Pfizer, Novartis, Boehringer Ingelheim, Roche, and Takeda Pharmaceuticals; and receiving research funding from Novartis, AstraZeneca, GlaxoSmithKline, Bayer, and Pfizer. RAS reports being on advisory board for Amgen, AstraZeneca, Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Taiho, Takeda Pharmaceuticals, and Yuhan; and receiving research grant support from AstraZeneca and Boehringer Ingelheim. KP reports receiving research funding from Alkem Laboratories, BDR Pharmaceutics, Biocon, Dr. Reddy’s Laboratories, Fresenius Kabi, Natco Pharma, and Roche. AK reports having employment (full time) in AstraZeneca Pharma India Ltd. RH reports having employment (full time) in AstraZeneca Plc.; and stock ownership for Allogene Therapeutics, AstraZeneca, CStone Pharmaceuticals, GlaxoSmith Kline Plc, Imugene Limited, Innate Pharma, Swedish Orphan Biovitrium AB, Chinook Therapeutics, and Adaptimmune Therapeutics. BCC reports receiving research funding from Novartis, Bayer, AstraZeneca, Mogam Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono Pharmaceuticals, Dizal Pharma, Merck Sharp & Dohme, AbbVie, Medpacto, GI Innovation, Eli Lilly, Blueprint Medicines, and Interpark Bio Convergence Corp.; having consulting role for Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Ono Pharmaceuticals, Yuhan, Pfizer, Eli Lilly, Janssen, Takeda, Merck Sharp & Dohme, Janssen, Medpacto, and Blueprint Medicines; having stock ownership for TheraCanVac Inc., Gencurix Inc., Bridgebio Therapeutics, Kanaph Therapeutic Inc., Cyrus Therapeutics, and Interpark Bio Convergence Corp.; being on scientific advisory board for Kanaph Therapeutic Inc., Brigebio Therapeutics, Cyrus Therapeutics, and Guardant Health; serving as board of director for Gencurix Inc. and Interpark Bio Convergence Corp.; having royalty for Champions Oncology; and serving as founder for DAAN Biotherapeutics. HCO declares no conflict of interest.

© The Author(s), 2022.

Figures

Figure 1.
Figure 1.
Region-wise prevalence of (a) EGFR testing and (b) EGFR mutations. EGFR, epidermal growth factor receptor; EGFRwt, EGFR wild-type.
Figure 2.
Figure 2.
Kaplan–Meier plot of total PFS and OS after initial therapy by EGFR type before propensity score matching: (a) rwPFS in overall patients with stage III NSCLC. Kaplan–Meier survival curves for progression-free survival for all stage III NSCLC patients with EGFRm and EGFRwt are shown in blue or red, respectively. Median rwPFS for EGFRm, 14.0 months (95% CI: 12.4–15.7). Median rwPFS for EGFRwt, 12.2 months (95% CI: 11.4–13.4). (b) OS in overall patients with stage III NSCLC.Kaplan–Meier survival curves for overall survival for all stage III NSCLC patients with EGFRm and EGFRwt are shown in blue or red, respectively. mOS for EGFRm, 50.3 months (95% CI: 44.8–66.7). mOS for EGFRwt, 40.0 months (95% CI: 33.2–47.9). CI, confidence interval; EGFRm, epidermal growth factor receptor mutation; EGFRwt, EGFR wild-type; mOS, median overall survival; NSCLC, non-small-cell lung cancer; OS, overall survival; rwPFS, real-world median progression-free survival.
Figure 3.
Figure 3.
Kaplan–Meier plot of PFS and OS in unresectable stage III patients with and without EGFRm following cCRT and cCRT or EGFR-TKI as initial therapy: (a) rwPFS following cCRT Kaplan–Meier survival curves for PFS following cCRT for stage III NSCLC patients with EGFRm and EGFRwt are shown in blue or red, respectively. Median rwPFS for EGFRm, 10.5 months (95% CI: 5.6–16.6). Median rwPFS for EGFRwt, 10.8 months (95% CI: 9.0–12.7). (b) OS following cCRTKaplan–Meier survival curves for OS following cCRT for stage III NSCLC patients with EGFRm and EGFRwt are shown in blue or red, respectively.mOS for EGFRm, 48.0 months (95% CI: 47.2–NC).mOS for EGFRwt, 36.5 months (95% CI: 28.9–NC).(c) rwPFS following cCRT or TKI monotherapyKaplan–Meier survival curves for PFS for stage III NSCLC patients with EGFRm following cCRT and TKI monotherapy without irradiation are shown in blue or red, respectively. Median rwPFS for cCRT, 10.5 months (95% CI: 5.6–16.6). Median rwPFS for TKI monotherapy without irradiation, 14.6 months (95% CI: 8.9–19.3). (d) OS following cCRT or TKI monotherapy. Kaplan–Meier survival curves for OS following cCRT for stage III NSCLC patients with EGFRm and EGFRwt are shown in blue or red, respectively. mOS for EGFRm, 48.0 months (95% CI: 47.2–NC). mOS for TKI monotherapy without irradiation, 24.0 months (95% CI: 15.7–NC). cCRT, concurrent chemoradiotherapy; CI, confidence interval; EGFRm, epidermal growth factor receptor mutation; EGFRwt, epidermal growth factor receptor wild-type; mOS, median overall survival; NC, non-calculable; NSCLC, non-small-cell lung cancer; OS, overall survival; PFS, progression-free survival; rwPFS, real-world PFS; TKI, tyrosine kinase inhibitor.
Figure 4.
Figure 4.
Initial therapy and second-line therapy post-progression. cCRT, concurrent chemoradiotherapy; Chemo, chemotherapy; CRT, chemoradiotherapy; TKI, tyrosine kinase inhibitor.

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