Use of tyrosine kinase inhibitors during pregnancy for oncogenic-driven advanced non-small cell lung carcinoma

Highlights

• Lung cancer during pregnancy is a rare event but its incidence is on the increase.

• TKIs should be proposed during pregnancy for oncogenic-driven advanced NSCLC.

• The maternal benefits should be weighed against fetal risks.

Abstract

Introduction

Lung cancer associated with pregnancy is rare but on the increase. The use of tyrosine kinase inhibitor (TKI) therapy for advanced oncogenic-driven non-small cell lung carcinoma (NSCLC) has improved overall survival. Oncological and obstetric outcomes of patients diagnosed with NSCLC and treated by TKIs during pregnancy have been poorly evaluated.

Methods

Three cases of NSCLC treated by TKIs during pregnancy were collected from the prospective database of the Cancer Associé à La Grossesse (CALG) network (France) in addition to eight cases identified by a systematic review performed between 2000 and 2021.

Results

Among the eleven reported patients, six received an EGFR- and five an ALK-TKI. All patients were young nonsmokers and four had brain metastases at diagnosis. TKI treatment was initiated during the first trimester for three patients. Premature delivery was induced in 10/11 patients. Anamnios occurred in one patient treated by osimertinib and trastuzumab. Five newborns were hypotrophic. No newborn malformations were observed. Diffusion of the TKIs, confirmed by blood cord sampling, represented about 1/3 (EGFR-TKI) and 1/8 (ALK-TKI) of the maternal concentration. No developmental abnormalities were observed in the children (follow-up 30 months). The anti-tumor efficacy and tolerance of TKIs, when reported, appears similar to that described in the general population.

Conclusions

Our results support the rationale for using TKIs during pregnancy, both in terms of maternal NSCLC disease control and the relatively mild effects on the fetus. Our data will serve to better inform patients about the risks associated with TKIs used during pregnancy, contributing to shared decision making.

Introduction

Lung cancer is the most frequent cancer and cause of cancer death in men and women combined[1], [2]. In women, it is the third most common cancer type (770 828 new cases in 2020) and the second most common cause of cancer death[1], [2]. In France, the incidence and mortality of lung cancer rose by 5.3% and 3.5%, respectively, for women between 1998 and 2010, and it was responsible for 10 356 deaths in 2018[4]. Because of the smoking epidemic in women, most countries are observing an increasing incidence of lung cancer in women particularly in developing countries[1], [2]. While the majority of lung cancers are associated with tobacco smoking, the World Health Organization estimates that 25% of lung cancer worldwide occurs in never smokers[5]. This percentage is probably closer to 10–15% in Western countries, and varies widely from approximately 2–6% in men in Western series to more than 50% in women from Southeast Asia[5].

Overall, the estimated incidence of any cancer during pregnancy is 1/1000 pregnancies[6]. In France, while the exact incidence of lung cancers associated with pregnancy is unknown, it is estimated at around 3.5% by the French national network, Cancer Associé à La Grossesse (CALG)[6]. Lung cancer associated with pregnancy is a rare event but on the increase both because more young women are smoking and women are delaying having children till later in life[7], [8]. Lung cancers are also more frequently observed in women non-smokers than men non-smokers [9], [10]. Almost all are of the adenocarcinoma subtypes compared to NSCLC in smokers and appear to be a distinct disease caused by oncogenic drivers[9], [10], [11]. The two main known oncogenic drivers are EGFR (Epidermal Growth Factor Receptor) mutations and ALK (Anaplastic Lymphoma Kinase) fusions present, respectively, in 10 to 20% (up to 40% in Asians), and 2 to 7% of NSCLC in Caucasians and Asians [12]. EGFR mutations are more frequent in women while ALK fusions are more frequent in young patients[9], [10], [12]. Many small molecule kinase inhibitors have been developed to target these molecular alterations[12]. They now represent the first-line treatment for advanced stage NSCLC with oncogenic driver increasing overall survival compared with the standard platinum-based doublet chemotherapy[12].

During pregnancy, most lung cancers are diagnosed at advanced stage raising a major medical challenge about how to best manage the maternal disease while limiting the impact on fetal outcomes[6], [7], [8]. While considerable data have been accumulated regarding the use of chemotherapy during pregnancy, little is known about the use of small molecule kinase inhibitors in such a setting[13]. Therefore, the aim of the current study was to describe the oncological and obstetric outcomes of patients diagnosed with oncogenic-driven advanced NSCLC treated by kinase inhibitors during pregnancy and especially authorized ALK/EGFR tyrosine kinase inhibitors (TKI) using the prospective database of the CALG network.

We queried the prospective database of the CALG network (Tenon Hospital, Sorbonne University, Paris, France) with the term “pregnant patients with lung cancer receiving a kinase inhibitor”. The CALG network was established in 2008 to investigate oncological and obstetric care, and maternal and neonatal outcomes in women with a cancer associated with pregnancy. The CALG database collects cases of cancers associated with pregnancy or diagnosed during the first postpartum year. All patients received clear and complete information and gave their consent. The Ethics Committee (CEROG) of the Collège National des Gynécologues et Obstétriciens Français (CNGOF) approved the study (CEROG-2019-GYN-603).

Patients diagnosed with a lung cancer associated with pregnancy between January 2011 and September 2020, and for whom advice was requested from the CALG network, were eligible for participation. Subsequently, only patients who received a TKI during pregnancy were analyzed. Exclusion criteria were patients with lung cancer associated with pregnancy not receiving a TKI and patients diagnosed with lung cancer during the first postpartum year.

Lung cancer diagnosis was systematically proven by histology. The following data were recorded: age, parity at diagnosis, smoking, familial and personal history of cancer, obstetric history, term at diagnosis, exams performed during pregnancy, lung cancer disease stage using the 8th edition of the lung cancer TNM staging, pathological and molecular features of the cancer, treatment regimen received during the pregnancy and in the postpartum period, term and mode of delivery, and neonatal and maternal outcomes. Maternal as well umbilical cord blood plasma concentrations of TKIs were reported if available. The clinical status of patients and children were updated in April 2021.

We used the methodology recommended by the Prisma statement for reviews and meta-analyses. The literature research was conducted in Medline, Embase and the Cochrane Library and was limited to studies published in English and French between January 2000 and April 2021. The MeSH Database of Pubmed helped steer the search by combining the following MeSH keywords: ‘‘lung cancer’’, ‘‘women’’, ‘‘pregnancy’’ and ‘‘tyrosine kinase Inhibitor’’, “kinase inhibitor”, “afatinib”, “alectinib”, “dacomitinib”, “brigatinib”, “dabrafenib”, “ceretinib”, “crizotinib”, “erlotinib”, “gefitinib”, “lorlatinib”, “osimertinib” and “vemurafenib” Fig. 1. Only original studies reporting pregnant patients treated by a market authorized TKI for lung cancer were retained. Other studies were not analyzed (Supplementary data).