Treating anaplastic lymphoma kinase (ALK) fusion-driven metastatic non-small cell lung cancer (NSCLC) with alectinib through pregnancy

Abstract

Management of cancer during pregnancy requires careful consideration of risks and benefits from maternal and fetal perspectives. For advanced lung adenocarcinomas, with no targetable driver mutations, there is evidence-based guidance on the use of carboplatin–paclitaxel chemotherapy after first trimester. In contrast, for epidermal growth factor receptor (EGFR)-mutated or anaplastic lymphoma kinase (ALK)-rearranged metastatic lung adenocarcinomas, there is a paucity of clinical data on the safety of EGFR and ALK tyrosine kinase inhibitors to mother and fetus for official guidelines to recommend the use of these otherwise-first-line therapies in pregnancy. Considering this knowledge gap, we present a case of a young gravida 1 para 0 (G1P0) woman who continued alectinib 300 mg oral two times per day for ALK-rearranged metastatic lung adenocarcinoma throughout all 36 weeks of her pregnancy and delivered a healthy baby at term via caesarean section (C-section).

Background

Cancer during pregnancy is uncommon—with estimated incidence rates of about 1 in every 1000–4000 pregnant women.^1–3 The more common cancer diagnoses during pregnancy include breast cancers (40%), lymphomas and leukaemias (20%), gynaecological cancers (17%), and melanoma (5%). In comparison, lung cancers in pregnancy are rare (<1%),^{3 4} and there is comparably scant literature to guide management strategies for these patients. Since pregnant patients are almost invariably excluded from clinical trials, safety data regarding the placental-to-fetal transfer, teratogenicity and embryotoxicity of cancer drugs is largely based on animal studies, ex vivo studies (eg, measuring fetal transfer rates using human perfused cotyledon models) or clinical case reports (eg, comparing in vivo concentrations of drug in maternal serum, placental tissue, cord blood and amniotic fluid).⁴

Currently, the published guidance on the prepartum use of chemotherapies is clearer than for targeted agents including tyrosine kinase inhibitors (TKIs) in all cancer types.² Cytotoxic chemotherapies in general are contraindicated until after first trimester, with fetal malformation risks dropping from 10%–20% in first trimester to 1.3% in third trimester.¹ For advanced non-small cell lung cancer (NSCLC) specifically, combination of carboplatin–paclitaxel chemotherapy can be used after first trimester, while TKIs including epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) inhibitors are currently discouraged throughout pregnancy given the lack of supporting data.^{1 4} For pregnant patients diagnosed with advanced lung adenocarcinomas with targetable EGFR mutations or ALK fusions—for which there is clinical trial evidence showing superior survival outcomes with TKIs compared with chemotherapy^5–10—this creates pressure to choose induced prematurity in order to expedite postpartum first-line TKI therapy, or choose inferior chemotherapy as first-line therapy until delivery.

Case presentation

A young woman presented with progressive fatigue, dry cough, pleurisy and haemoptysis. She was found to have a 5.3 cm left hilar mass that invaded her left lower lobe (LLL) pulmonary artery and encased her LLL bronchus with 75% narrowing. At the time of diagnosis, she had a malignant left-sided pleural effusion, mediastinal lymphadenopathy, a solitary liver metastasis and bony metastases. Biopsy of the hilar mass showed ALK-rearranged lung adenocarcinoma. She was started on first-line crizotinib therapy.

She remained on crizotinib for 17 months, before she had radiological progression with asymptomatic brain metastases. She was switched to second-line alectinib at 600 mg orally two times per day, which led to a complete radiological response (figure 1A,B). She later required a dose reduction to 300 mg orally two times per day due to hyperbilirubinaemia (common terminology criteria for adverse events, grade 2), with ongoing intracranial disease control (figure 1C).

Figure 1.

Serial imaging showing response of brain metastases to alectinib, achieved prior to pregnancy (A, B) and maintained throughout pregnancy (C, D). MP-RAGE GAD, Magnetization Prepared - RApid Gradient Echo with gadolinium.

After 49 months on alectinib, she was unexpectedly found to be pregnant. She was seen in consultation by the maternal fetal medicine team. The risks of alectinib in pregnancy for mother and fetus remain largely unknown, with a literature review done at the time yielding only preclinical studies showing possible fetal loss with no confirmed mechanism of teratogenicity, while a single clinical case report¹¹ described good fetal outcome. After weighing uncertain risks against expected benefits, the patient and her medical team decided to continue alectinib treatment, at the 300 mg orally two times er day dose, to preserve her state of cancer remission. On alectinib, she did not experience radiological or clinical recurrence of brain metastases until after her pregnancy (figure 1C,D).

Outcome and follow-up

During her pregnancy, she had two episodes of recurrent haemoptysis at 17+4 gestational age (GA) and at 24+1 GA, attributed to bronchial artery hypertrophy and increased blood volume from pregnancy. The second episode was significant enough that required inpatient monitoring in a high acuity unit. Left-sided bronchial artery embolisation was considered, but ultimately, she was treated conservatively and had no recurrence of haemoptysis in her third trimester.

Her fetal anatomy ultrasound at 20 weeks+0 days GA showed no abnormalities. Obstetrical ultrasounds showed normal placenta, amniotic fluid, fetal movements, umbilical artery Doppler, fetal anatomy, fetal growth (between 92% and 97% percentile from 29+3 to 36+0 GA) and 8/8 biophysical profiles.

She was planned for an elective C-section at 38+6 GA, but experienced term premature rupture of membranes and, therefore, underwent an emergency primary lower-segment C-section at 37+0 GA. Birth weight was 3610 g and Appearance, Pulse, Grimace, Activity and Respiration score was 8 and 9. Pathological exam of placenta showed focal chronic lymphohistiocytic villitis, with no evidence of metastasis.

Currently, the baby is healthy and meeting 26-month developmental milestones.

Discussion

To our knowledge, there are only three other published case reports of women receiving lengthy courses (>30 weeks) of alectinib treatment for ALK-rearranged metastatic NSCLC during pregnancy. The first published case from Italy involved a similar duration of in utero exposure of alectinib (35 weeks and 5 days).¹¹ Another case from Belgium reported a shorter 32 weeks of in utero exposure of alectinib.¹² A third case from France involved a very short duration of in utero exposure of alectinib (22 days only).¹³ Boudy et al ¹³ also identified three additional cases where patients received short courses (3–5 weeks) of first-generation ALK inhibitors (crizotinib or ceritinib) for ALK-rearranged metastatic NSCLC during pregnancy.^13–15 In contrast, at least eight published case reports identified by Boudy et al ¹³ involved expediting delivery, sometimes with induced premature delivery, to allow initiation of indicated TKI therapy in the postpartum setting.¹²

In table 1, we compare our case against those six published case reports.^11–15 Only one of these prior cases had a comparably lengthy in utero exposure to alectinib of about 36 weeks. In our case, C-section was prompted by term premature rupture of membranes, while the case reported by Scarfone et al ¹¹ was complicated by fetal acute respiratory distress syndrome. The other four cases had shorter in utero drug exposure—less than 4 weeks in four cases^13–15 and 32 weeks in De Smedt et al ¹² where alectinib was stopped about 5 weeks prior to delivery after weighing disease stability against unknown effects on fetal development. Reassuringly, circulating TKI concentrations in cord blood and amniotic fluid has been reported to be <9% of that in maternal blood.^{11 13} Collectively, child development has been noted to be within normal range at 10–29 months postpartum follow-up. Ongoing follow-up will be required to rule out long-term effects of in utero exposure of ALK inhibitors.

Table 1.

Case reports of lung cancer treated with ALK inhibitors during pregnancy

Case	Current case report	De Smedt et al 2023 12	Boudy et al 2021 Case 113	Boudy et al 2021 Case 313	Scarfone et al 202111	Padrão et al 201814	Jensen et al 201915
Non-small cell lung cancer diagnosis	Adenocarcinoma with ALK rearrangement, metastatic to pleura, liver and bone.	NSCLC with ALK translocation, metastatic to axilla and subdiaphragmatic nodes.	Muco-epidermoid carcinoma, EML4-ALK fusion, metastatic to liver and bone.	Adenocarcinoma, with ALK rearrangement, metastatic to brain and breast.	Adenocarcinoma, with EML4-ALK fusion, metastatic (not otherwise specified).	Adenocarcinoma, with EML4-ALK fusion, metastatic with pleural effusion.	Adenocarcinoma, with EML4-ALK fusion, metastatic to bone, mediastinum, liver.
ALK TKI treatment	2L Alectinib 300 mg orally two times per day (started years before conception)	1L Alectinib 600 mg orally two times per day (started months before conception, stopped at 32 GA)	2L Alectinib 600 mg orally two times per day (started at 33 GA, post-1L cisplatin–paclitaxel)	2L Ceritinib 450 mg orally once a day (started at 31 GA, post-1L Crizotinib)	1L Alectinib 600 mg orally two times per day (started 12 weeks pre-conception)	1L Crizotinib 250 mg orally once a day (started at 26 GA)	1L Crizotinib 250 mg orally once a day (started at 23 GA)
Antepartum	36 weeks	32 weeks	22 days	35 days	35 weeks 5 days	~4 weeks	~3 weeks
Post partum	Continued till 2 months pp (with PD, switched to brigatinib).	Restarted	Continued	Continued till 18 pp (with PD, switched to lorlatinib).	Continued	Continued till 15 days pp (with PD, switched to chemotherapy).	Continued
	Concentration of TKI at delivery
Maternal blood	–	–	482 ng/mL	–	259 ng/mL	–	–
Cord blood	–	–	40 ng/mL	–	18 ng/mL	–	4 ng/mL
Amniotic fluid	–	–	–	–	23 ng/mL	–	–
Delivery	C-section at 36 GA (term PROM)	Induced at 36+6 GA	C-section at 36 GA (thrombocytopenia)	C-section at 36 GA (elective)	C-section at 35+5 GA	C-section at 30 GA (cancer progression)	C-section at 26+2 GA (HELLP syndrome)
Birth weight	3610 g	Eutrophic	2150 g (7th percentile)	2950 g (60th percentile)	–	–	700 g (−28th percentile)
APGAR	8/9	7/10	10/10/10		–	–	5/9/10
	Fetal anomalies and Complications
Prenatal	None	None. Fetal MRI brain normal.	None	None	None	None	unknown
Peridelivery	None	None. No malignant cells in placenta.	None. No malignant cells in placenta.	Familial hexadactyly.	ARDS requiring NIV and surfactant. No malignant cells in placenta.	Adenocarcinoma cells identified in placenta.	Adenocarcinoma cells identified in placenta.
Postnatal	Normal development at 20 months	Normal development at 1 year.	Normal development at 11 months.	Normal development at 30 months.	Small laterocervical fistula at 3 months, treated conservatively. Normal development at 20 months.	Regular development at 29 months.	Regular development at 18 months.

ALK, anaplastic lymphoma kinase; APGAR, Appearance, Pulse, Grimace, Activity and Respiration score; ARDS, acute respiratory distress syndrome; ELM4, Echinoderm microtubule-associated protein-like 4; GA, gestational age; HELLP syndrome, haemolysis, elevated liver enzymes, low platelets syndrome; NIV, non-invasive ventilatory support; NSCLC, non-small cell lung cancer; PD, progressive disease; pp, post partum; PROM, premature rupture of membranes; TKI, tyrosine kinase inhibitor.

In conclusion, pregnant patients with ALK-rearranged advanced lung adenocarcinomas face a clinical dilemma. From a maternal perspective, targeted therapy in the form of ALK inhibitors is associated with superior survival outcomes compared with chemotherapy; but from a fetal perspective, there is a lack of safety data in terms of teratogenicity and embryotoxicity from in utero exposure. With this case report, we present our experience balancing these expected benefits against unknown risks. Our patient continued alectinib treatment at 300 mg orally two times per day, already dose-reduced for hepatotoxicity prior to conception, throughout all 36 weeks of her pregnancy. She delivered a healthy baby at term, who continues to meet developmental milestones as a 26-month-old.

Learning points.

• There are currently no clinical practice guidelines or consensus on whether it is safe from a fetal perspective to treat a pregnant woman with anaplastic lymphoma kinase (ALK)-rearranged lung cancer with ALK tyrosine kinase inhibitors (TKIs) (eg, alectinib) in the prepartum setting.

• Here, we present a case where lung cancer stability was achieved with 36 weeks of prepartum alectinib therapy, with normal child development at 10 months post partum.

• Until there are larger cohort data to firmly establish safety to fetus, our case report suggests that it may be safe to cautiously proceed with first-line ALK TKI therapy, if the unknown risks and expected benefits are acceptable to the patient, with multidisciplinary guidance from fetal–maternal medicine.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).