DOI: 10.1111/ajco.12853
SUPPLEMENT ARTICLE
Afatinib for an EGFR exon 20 insertion mutation: A case report of progressive stage IV metastatic lung adenocarcinoma with 54 months’ survival Raymond Tsz-Tong Chan Hong Kong Pacific Centre, Tsim Sha Tsui, Kowloon, Hong Kong
Abstract
Correspondence Dr. Raymond Tsz-Tong Chan, Suite 411, 4/F, Hong Kong Pacific Centre, 28 Hankow Road, Tsim Sha Tsui, Kowloon, Hong Kong. Email:
[email protected]
Non–small cell lung cancers (NSCLC) harboring the uncommon epidermal growth factor receptor
Funding Information Boehringer Ingelheim.
54 months, with 36 months on the second-generation TKI afatinib. Contrary to the existing liter-
(EGFR) exon 20 insertion mutations are generally thought to be unresponsive to EGFR-tyrosine kinase inhibitor (TKI) therapy. Presented here is a case of stage IV NSCLC harboring an uncommon EGFR exon 20 insertion mutation that was maintained at minimal progressive disease for ature, the patient in this case demonstrated a long, durable response to the EGFR-TKI, which was exhibited by a long survival endpoint. This suggests that stability in clinical symptoms might be sufficient to warrant continuation of therapy. KEYWORDS
afatinib, EGFR exon 20 insertion, epidermal growth factor receptor (EGFR), irreversible EGFR inhibitor, tyrosine kinase inhibitor (TKI), uncommon EGFR mutation
1
INTRODUCTION
uncommon EGFR exon 20 insertion mutation that was maintained at minimal progressive disease (PD) for 54 months, including 36 months
Non–small cell lung cancers (NSCLC) harboring the uncommon epi-
with the second-generation TKI afatinib.
dermal growth factor receptor (EGFR) exon 20 insertion mutations are generally thought to be unresponsive to EGFR-tyrosine kinase inhibitor (TKI) therapy.1 The uncommon exon 20 insertion mutations
2
CASE REPORT
represent approximately 9% of all EGFR mutations, and is the third most common group of EGFR mutations, after exon 19 deletions and
A 55-year-old female nonsmoking patient was diagnosed in Febru-
L858R.1 Prognosis of exon 20 insertion mutations is usually poor,
ary 2013 with stage IV intrathoracic metastatic lung cancer and
for example one retrospective subgroup analysis (n = 20) reported a
lymphangitis carcinomatosis, with a poor prognosis. Core biopsy
median overall survival (OS) of only 5 months (95% confidence interval
revealed adenocarcinoma with an EGFR exon 20 insertion muta-
[CI], 0.17–9.8 months).2 Although traditional chemotherapy and the
tion (A767_S768insSVA tandem duplication). From March to May
newer immunotherapy appear to be limited in their effects on and/or
2013, the patient had three cycles of chemotherapy with peme-
matching with tumor types, recent evidence from the LUX-Lung 2, 3
trexed/carboplatin. Although cough, dyspnea and retrosternal dis-
and 6 studies subanalysis suggests that the second-generation irre-
comfort were reduced, a positron emission tomography/computed
versible EGFR-TKIs may have effects on tumors with these uncom-
tomography (PET/CT) scan showed PD. The patient declined further
mon mutations.3 The subanalysis included 75 patients (12% of 600
chemotherapy due to significant lethargy that left her homebound.
in the study population) who had uncommon EGFR mutations, with
The patient had erlotinib 150 mg daily from May 2013 to April
71.1, 14.3 and 8.7% response rates for point mutations or duplica-
2014. Although the PET-CT scan in July 2013 indicated minimal PD
tions in exons 18–21, de novo T790M mutations and exon 20 insertions,
(tumor enlarged 200 m and
and OS not reached at the 34.7 months median follow-up.3 Like-
endure long-haul travels, and started to gain weight in January 2015.
wise, a retrospective analysis of TKI-treated patients with an EGFR
Afatinib was well-tolerated in the patient, except for occasional diar-
exon 20 insertion (A763_Y764insFQEA) reported a median time-to-
rhea (mostly mild) that was relieved with antidiarrheals.
progression (TTP) of 5.0 months (95% CI, 2.9–7.1 months; n = 11) and
The patient was seen monthly and continued to show stable
an OS of 24.0 months (95% CI, 19.1–28.9 months; n = 8).8 Heigener
disease (SD) with symptom improvement until May 2016, when
et al.9 reported response to third- or fourth-line afatinib in pretreated
decreased appetite was followed by weight loss, low-grade fever
NSCLC patients with uncommon mutations, with 22% (n = 58) show-
and posterior chest pain. In view of the reports of EGFR muta-
ing a partial response, but with an OS of only 3.8 months (n = 60;
tions responding to EGFR-TKI + bevacizumab (including exon 19
range: 0.2–24.6 months). Although EGFR uncommon mutations exist
deletion, exon 21 L858R, L861Q, and exon 18 G719S mutations),5,6
as a heterogeneous variety, and it is difficult to document the objective
one injection of bevacizumab was given, but without response. The
response rate (ORR) for each mutation, it appears that OS can never-
patient experienced episodes of chest infections (Figure 1), and
theless be prolonged with TKI therapy; in our case, it was the second-
a PET-CT scan in March 2017 showed significant PD, accompa-
generation irreversible inhibitor afatinib.
nied by severe symptoms of deterioration including muscle loss
Unlike in most clinical trials, where TKI therapy terminates when
and hypoxia. In April 2017, repeated liquid biopsy with next-
the patient reaches PD, our patient continued therapy at SD with
generation sequencing (NGS) returned the same mutation results. In
minimal radiological progression until significant symptom deteri-
April 2017, afatinib was stopped and the patient was given gemc-
oration, which occurred almost 4 years later. This suggests that
itabine/carboplatin/bevacizumab. In view of recent strong randomized
stability in clinical symptoms might be sufficient to warrant contin-
controlled trial evidence of pembrolizumab + chemotherapy treat-
uation of therapy. The LUX-Lung 5 trial studied the effects of con-
ment for NSCLC,7 the second and third gemcitabine/carboplatin cycles
tinuing afatinib in treatment-experienced (≥1 line of chemotherapy,
were combined with pembrolizumab injection, without success. The
erlotinib/gefitinib and afatinib) patients beyond progression, with afa-
patient died in July 2017 from a chest infection.
tinib + paclitaxel versus single-agent chemotherapy, and found significant improvements in PFS (median 5.6 vs. 2.8 months, hazard ratio [HR] = 0.60, P = 0.003) and ORR (32.1 vs. 12.3%, P = 0.005), although not in OS.10
3
DISCUSSION
In scenarios where a partial response has not been attained (i.e. tumor has not shrunken by >30%) with the available therapies, it
Contrary to reports in the existing literature, our lung cancer patient
might be possible to maintain a SD via a combination of symptomatic
harboring an uncommon EGFR mutation demonstrated a long, durable
stability and treatment tolerance. First, during first-line chemother-
response to an EGFR-TKI, with a long survival. This case contains sev-
apy in our patient, although symptoms were slightly improved and
9
CHAN
laboratory measurements remained within acceptable ranges, she progressed radiologically and experienced severe lethargy as a side effect of chemotherapy with deteriorated health. Switching to erlotinib and later afatinib appeared to have prevented further deterioration from this side effect. Second, the patient showed very good tolerance to afatinib, which might have contributed to maintaining the body's response to the drug for an extended period. In fact, this patient appeared to have deteriorated in a step-wise fashion after each episode of chest infection (which was settled with antibiotics). Although the bacterial infections were unlikely treatment-related, it is unclear what caused the patient to become increasingly prone to them, and whether they diminished the patient's response to therapy. A clearer understanding of the underlying causality would likely help to further delay PD.
ACKNOWLEDGMENTS The author would like to thank Best Solution for editorial assistance, which was funded by Boehringer Ingelheim (B.I.). This research did not receive any specific grants from funding agencies in the public, commercial or not-for-profit sectors.
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4. Harada T, Lopez-Chavez A, Xi L, et al. Characterization of epidermal growth factor receptor mutations in non-small-cell lung cancer patients of African-American ancestry. Oncogene. 2011;30:1744– 1752. 5. Seto T, Nishio M, Atagi S, et al. Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-smallcell lung cancer harbouring EGFR mutations (JO25567): an open-label, randomised, multicentre, phase 2 study. Lancet Oncol. 2014;15:1236– 1244. 6. Otsuka K, Hata A, Takeshita J, et al. EGFR-TKI rechallenge with bevacizumab in EGFR-mutant non-small cell lung cancer. Cancer Chemother. Pharmacol. 2015;76:835–841. 7. Langer CJ, Gadgeel SM, Barghaei H, et al. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous nonsmall-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016;17:1497–1508. 8. Lin YT, Liu YN, Wu SG, et al. Epidermal growth factor receptor tyrosine kinase inhibitor-sensitive exon 19 insertion and exon 20 insertion in patients with advanced non-small-cell lung cancer. Clin Lung Cancer. 2017;18:324–332. 9. Heigener DF, Schumann C, Sebastian M, et al. Afatinib in non-small cell lung cancer harboring uncommon EGFR mutations pretreated with reversible EGFR inhibitors. Oncologist. 2015;20:1167–1174. 10. Schuler M, Yang YC, Park K, et al. Afatinib beyond progression in patients with non-small-cell lung cancer following chemotherapy, erlotinib/gefitinib and afatinib: phase III randomized LUX-Lung 5 trial. Ann Oncol. 2016;27:417–423.
How to cite this article:
Chan RT. Afatinib for an EGFR
exon 20 insertion mutation: A case report of progressive stage IV metastatic lung adenocarcinoma with 54 months’ survival. Asia-Pac J Clin Oncol. 2018;14:7–9. https://doi.org/10.1111/ajco.12853
