Introduction
Alectinib is a highly selective and potent tyrosine kinase inhibitor that targets both anaplastic lymphoma kinase (ALK) and the rearranged during transfection (RET) oncogene products [1, 2]. Alectinib monotherapy is approved in the United States (US) and European Union (EU) as a first-line and later-line treatment for adults with advanced/metastatic ALK-positive non-small cell lung cancer (NSCLC) at a recommended dose of 600 mg taken orally twice daily (BID) [3, 4]. However, previous in vitro research has shown that the half maximal inhibitory concentration (IC50) of alectinib for RET is greater than that for ALK (4.8 vs. 1.9 nmol/l, respectively), suggesting the need to explore a higher dose for the treatment of patients with advanced RET fusion-positive NSCLC [1].
The Blood First Assay Screening Trial (BFAST; NCT03178552) is an open- label, multi-cohort study investigating the activity of multiple targeted therapies or immunotherapy in patients with unresectable, advanced or metastatic NSCLC who are screened for actionable genetic alterations exclusively using next-generation sequencing (NGS) of circulating tumour DNA (ctDNA) [5]. Seven interventional BFAST cohorts and one natural history cohort have been initiated to date, including ALK-positive, RET fusion-positive, high blood-based tumour mutational burden, ROS1-positive, v-raf murine sarcoma viral oncogene homologue B1 (BRAF) V600 mutation-positive, epidermal growth factor receptor (EGFR) exon 20 mutation-positive and Kirsten rat sarcoma virus (KRAS) G12C mutation-positive, each with their own treatment and biomarker-specific eligibility criteria [5–7]. Previously published outcomes from the ROS1-positive and ALK-positive cohorts of the BFAST study have shown the clinical feasibility of blood-based NGS in identifying patients with ROS1-positive NSCLC to be treated with entrectinib and ALK-positive NSCLC to be treated with alectinib, respectively [6, 8].
When the BFAST study was initiated in 2017, treatment options were limited for patients with advanced RET fusion-positive NSCLC because platinum-based chemotherapy was the only standard of care for treatment-naïve patients. Subsequently, specific RET inhibitors such as pralsetinib and selpercatinib have demonstrated clinically meaningful activity in RET fusion-positive NSCLC and have thus been approved in the US and EU for the treatment of advanced/metastatic RET fusion-positive NSCLC [9–13].
Herein, we present results from BFAST Cohort B (alectinib in RET fusion-positive NSCLC), which was planned to comprise a Phase I dose-escalation phase followed by a Phase II dose expansion at the recommended Phase II dose. However, enrolment to this cohort was closed prematurely and the dose-expansion phase was not initiated due to the clinical development of pralsetinib and selpercatinib, which were not available when the BFAST study was initiated.
Material and methods
Study design and treatment
Blood First Assay Screening Trial (NCT03178552) is an ongoing, open-label, global, multicohort study; patients that were identified as having unresectable, advanced/metastatic RET fusion-positive NSCLC by blood-based NGS were enrolled into Cohort B of BFAST. The global, single-arm BFAST Cohort B study consisted of a Phase I dose-escalation step followed by a Phase II dose- expansion study at the recommended Phase II dose. Staggered enrolment was employed in Phase I to ensure that a maximum of two patients received treatment simultaneously during the dose-limiting toxicity (DLT) assessment window (Cycle 1, Days 1–28). The dose-limiting toxicity were defined as adverse events (AEs) assessed by the investigator to be at least possibly attributable to alectinib, including Grade 3/4 myelosuppression events or Grade ≥ 3 non-haematological toxicities.
The initial dose of alectinib to be tested in Phase I was 900 mg BID given orally with food until progressive disease (PD), unacceptable toxicity, or withdrawal of consent. The study protocol was designed to potentially test a dose of up to 1200 mg BID and allowed for dose reduction in cases of unsatisfactory tolerability.
Patients
Eligible patients were aged ≥ 18 years, with histologically or cytologically confirmed stage III/IV RET fusion-positive NSCLC, confirmed by a central blood-based ctDNA NGS assay, an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0–2, life expectancy ≥ 12 weeks, and measurable disease according to Response Evaluation Criteria in Solid Tumours (RECIST) v1.1. Patients with asymptomatic brain or leptomeningeal metastases at baseline were allowed to enrol. Prior systemic treatment for advanced or metastatic NSCLC was not permitted.
The protocol was approved by the institutional review board at each study site, and the study was conducted in accordance with the principles of the Declaration of Helsinki. Written informed consent was obtained from all patients before initial blood screening and enrolment into a treatment cohort.
Endpoints
The primary endpoint of BFAST Cohort B was confirmed objective response rate (ORR) per investigator, defined as the proportion of patients with a complete response or partial response according to RECIST v1.1 on two assessments separated by ≥ 4 weeks. Secondary endpoints included the following: investigator-assessed duration of response (DoR), clinical benefit rate (CBR), and progression-free survival (PFS); independent review facility- assessed confirmed ORR, DoR, CBR, and PFS; overall survival; percentage of patients with AEs/safety; and the pharmacokinetic (PK) profile of alectinib. Safety was determined by the occurrence of any DLTs associated with alectinib at escalating doses. Incidence, type, and severity of AEs were based on the National Cancer Institute Common Terminology Criteria for AEs (V4.0).
Assessments
Patients were screened for actionable RET fusions using the Foundation Medicine Assay for Circulating Tumour DNA (FoundationACT™), a hybrid capture-based NGS assay, which was an earlier version of the FoundationOne®Liquid CDx assay (Foundation Medicine). FoundationACT™ was validated for genomic profiling of ctDNA from blood and demonstrated rearrangement detection at 100% sensitivity for mutation allele frequencies ≥ 0.5% [14]. Tumour assessments were performed at baseline and every 8 weeks during the study. Magnetic resonance imaging of the brain was required at each tumour assessment, irrespective of baseline central nervous system (CNS) disease status. Safety was assessed by the occurrence of any DLTs and by the incidence, type, and severity of AEs, including serious adverse events (SAEs) and AEs of special interest, which were graded according to the National Cancer Institute Common Terminology Criteria for AEs (v4.0) and encoded using the Medical Dictionary for Regulatory Activities (v22.0). Changes in vital signs, physical findings, and clinical laboratory results during and following administration of alectinib were also recorded.
Statistical analyses
No formal anti-tumour activity or PK analysis was performed due to early closure of the cohort. Tumour assessment data for the intent-to-treat population were provided descriptively. Safety analyses were performed on the safety-evaluable population and included all patients who received at least one dose of study drug.
Results
Patient disposition and demographics
Between 1 September 2017 and 27 February 2019, 40 out of 3787 screened patients were identified as RET fusion- positive (prevalence: 1.06%); eight of these patients were enrolled into the Phase I dose-escalation part of BFAST Cohort B (RET fusion-positive) and received alectinib at a dose of 900 mg BID. Patients had a median age of 62.5 years, and all had stage IV lung adenocarcinoma; five patients (62.5%) had CNS disease at baseline. Most patients were white, never smokers, and had a baseline ECOG PS of 1 (Table 1). The most common RET fusion partner was KIF5B (87.5%). No patients were enrolled into the Phase II dose expansion.
Table 1
Baseline demographics and clinical characteristics of the Blood First Assay Screening Trial Cohort B patients
Safety
At the data cut-off date (27 February 2019), mean treatment duration was 3.9 months (range: 0–8 months) with a mean number of doses of 224. Overall, the safety profile was in line with what has previously been reported in Phase III studies of alectinib (600 mg BID), and no new safety signals were observed [15–17]. All eight patients experienced at least one AE, including six (75.0%) who reported AEs potentially related to treatment (Table 2). Seven patients (87.5%) had Grade ≥ 3 AEs, and none of the Grade ≥ 3 AEs were experienced by more than one patient (Table 2). The most common AEs of any grade occurring in more than one patient were constipation (5 patients, 62.5%) and dyspnoea (four patients, 50.0%) (Table 3).
Table 2
Summary of adverse events in the Blood First Assay ScreeningTrial Cohort B patients
Table 3
Adverse events experienced by at least two patients
One DLT of death (unknown cause) occurred among the six DLT-evaluable patients; this was recorded as a Grade five event and was considered by the investigator to be related to study treatment and the underlying disease. The patient died at home, and there was insufficient information available to the investigator to rule out the possibility that study treatment contributed to the event. Serious adverse events occurred in five patients (62.5%) (Table 2) and were considered related to study treatment in two patients (25.0%). The serious adverse events included death (nature of the event not known), general physical health deterioration, pneumonia, blood creatine phosphokinase increase, major depression, and dyspnoea (resulting in death).
Adverse events leading to withdrawal of alectinib were reported in three patients (37.5%; death [nature of the event not known], general physical health deterioration, and dyspnoea), and four patients (50.0%) experienced AEs requiring dose modification of alectinib (blood bilirubin increased, blood creatine phosphokinase increased, vomiting, hypokalaemia, major depression, and rhabdomyolysis) (Table 2). Three patients who had AEs that may have been related to treatment required dose modification or interruption (Table 2). A total of four patients died (all cause), including three before the first tumour assessment. Causes of death were clinical progression, worsening dyspnoea and/or respiratory failure due to NSCLC, unknown death at home, and unknown death after PD in long-term follow-up. At the time of data cut-off, six patients had discontinued the study, five due to PD and one due to an AE. There were no AEs of special interest reported with alectinib.
Pharmacokinetics
A total of 54 PK samples were collected from the eight patients. Due to the limited number of patients with a full evaluable PK profile, no formal PK analysis was performed.
Anti-tumour activity
Confirmed best overall response (by investigator) in the five evaluable patients was stable disease (SD) in four patients and PD in one patient (Table 4). The three remaining patients died before their first tumour assessment. Two of the four patients with confirmed SD were reported to have an unconfirmed partial response.
Table 4
Best overall response and duration of response in the individual Blood First Assay Screening Trial Cohort B patients
| Patient | Confirmed best overall response* | Unconfirmed best overall response* | Maximum SLD change from baseline (%) | DoR* (months) |
|---|---|---|---|---|
| 1 | SD | PR | –44.67 | 1.9 |
| 2 | PD | PD | +53.85 | – |
| 3 | SD | SD | –7.45 | – |
| 4 | SD | PR | –43.83 | 1.8 |
| 5 | SD | SD | –22.84 | – |
Discussion
In patients with RET fusion-positive NSCLC, the limited anti-tumour activity observed with alectinib in this study does not justify further evaluation of this agent in this setting, where the selective RET inhibitors pralsetinib and selpercatinib have demonstrated greater clinical benefit than alectinib [18]. Four of the five evaluable patients experienced confirmed SD, including two patients with unconfirmed partial responses. The anti-tumour activity of alectinib was generally consistent with prior studies using doses of 450–900 mg BID in patients with RET- rearranged NSCLC [19, 20]. Preliminary anti-tumour activity was reported with alectinib administered at 600 mg BID (n = 3) or increased to 900 mg BID due to CNS relapse (n = 1) in a case series of four patients with advanced RET-rearranged NSCLC, three of whom had received prior RET inhibitors [20]. In a single-arm, open-label Phase I/II trial of alectinib dosed at 450 or 600 mg BID in 25 RET inhibitor-naïve Japanese patients with RET-rearranged NSCLC, one patient (4%) achieved an objective response and 13 (52%) had disease control at 8 weeks [19].
Blood-based NGS may offer a viable alternative to tissue-based testing in patients with advanced NSCLC, overcoming some of the challenges in obtaining tumour samples, because approximately 30% of patients with advanced or metastatic NSCLC lack sufficient tissue for comprehensive biomarker testing [21–24]. The Blood First Assay Screening Trial is the first trial to use prospective blood-based NGS as the sole method of identifying patients with NSCLC with actionable genetic alterations, and data from the BFAST ALK-positive and ROS1-positive cohorts support the clinical applicability of blood-based NGS to inform clinical decisions [6, 8]. The prevalence of RET fusion-positive NSCLC identified in this study using blood-based NGS (1.06%) is in alignment with the 1–2% RET fusion-positive prevalence reported elsewhere [25], and suggests that blood-based and tissue-based biomarker analyses yield similar detection rates.
In BFAST Cohort B, enrolment to the Phase I dose- escalation stage was closed prematurely based on limited clinical activity with 900 mg BID alectinib in patients with advanced RET fusion-positive NSCLC. Neither further dose escalation nor the Phase II dose expansion were initiated at the discretion of the sponsor, due to the evolving treatment landscape for patients with advanced RET fusion-positive NSCLC at the time. Given the low rate of DLTs in patients treated with alectinib 900 mg BID, escalation to 1200 mg BID could have occurred had the study continued. The 900 mg BID dose of alectinib is higher than the recommended dose of 600 mg BID for the treatment of patients with advanced ALK-positive NSCLC [3, 4].
The nature of the reported AEs in BFAST Cohort B was in line with the safety profile of alectinib observed in previous Phase III studies at the 600 mg BID dose [15–17]. Although the number of patients in BFAST Cohort B was very low, the incidence of Grade ≥ 3 AEs and SAEs (87.5% and 62.5%, respectively) was higher than that recorded for patients with ALK-positive NSCLC receiving alectinib 600 mg BID in the Phase III ALEX (52% and 39%, respectively) [15] or ALESIA studies (29% and 15%, respectively) [17]. his may be due to the higher peak concentrations and exposure levels of alectinib at the 900 mg BID dose relative to the 600 mg BID dose reported in an earlier Phase I dose-finding study [26], or it may indicate a relatively high tumour burden in our population of patients, most of whom had CNS metastases at presentation. Overall, no new safety signals emerged during this study.
Summary points
The multi-cohort BFAST is exploring the anti-tumour activity of targeted therapies or immunotherapy in patients with advanced/metastatic NSCLC using blood-based NGS as the sole method of identifying patients with actionable genetic alterations.
Alectinib 600 mg twice daily is approved for patients with advanced/metastatic ALK-positive NSCLC, but a higher alectinib dose may be required for the treatment of advanced RET fusion-positive NSCLC as the IC50 of alectinib for RET is greater than that for ALK.
The Blood First Assay Screening Trial Cohort B (RET fusion-positive), comprising Phase I dose escalation and Phase II dose expansion, was closed prematurely at the discretion of the sponsor due to emerging data from other RET inhibitors; eight patients received alectinib 900 mg BID in Phase I prior to cohort closure.
Among five efficacy-evaluable patients, confirmed investigator-assessed best overall response was SD in four patients (two of whom had an unconfirmed partial response) and PD in one patient.
One DLT (death due to unknown cause) occurred and was considered related to alectinib and the underlying disease.
Serious adverse events were reported in five patients (62.5%), which were considered related to alectinib in two patients (25.0%), and included death, general physical health deterioration, pneumonia, blood creatine phosphokinase increase, major depression, and dyspnoea (resulting in death).
Treatment-related AEs occurred in six patients (75.0%), three of whom required dose modification or interruption of alectinib.
No formal PK analysis was performed due to the limited number of evaluable patients.
Conclusions
Despite the early termination of BFAST Cohort B, alectinib 900 mg BID showed limited activity in patients with advanced RET fusion-positive NSCLC and no new safety signals were observed. However, as the clinical activity of alectinib was lower than that demonstrated with other RET inhibitors, further evaluation of alectinib in this patient population is not warranted. The limited data collection precludes any definitive conclusions regarding the benefit- risk profile of alectinib in this patient population.
