AXL Inhibitors in Oncology Clinical Trials: A Review

Abstract

The AXL receptor tyrosine kinase is a transmembrane protein commonly overexpressed in both solid and hematologic malignancies. AXL plays a role in malignant cell growth, survival, proliferation, and adaptive immunity. As such, AXL overexpression is correlated with a worse prognosis. Drugs impairing the function of AXL are currently in development as monotherapies and in combination with other agents and have displayed antitumor efficacy in preclinical models, including tumors with AXL overexpression. AXL inhibitors have demonstrated preliminary antitumor activity in clinical trials and have generally been well tolerated, with the most common side effects including neutropenia, diarrhea, fatigue, nausea, and anemia. This clinical review aims to provide a comprehensive summary of published information from clinical trials investigating AXL inhibitors as monotherapies or in combination regimens.

INTRODUCTION

The AXL gene, located on the 19th chromosome (19q13.2),[1] encodes a receptor tyrosine kinase (RTK) comprised of an extracellular domain, a transmembrane domain, and an intracellular domain.[2] The AXL receptor was first identified in 1988 in patients with chronic myeloid leukemia.[3] The receptor was designated as “AXL,” short for “anexelekto,” a Greek word meaning “uncontrolled,” reflecting the receptor’s overexpression and contribution to malignant cell proliferation.[2] Alternate mRNA splicing yields three unique AXL receptor tyrosine kinase isoforms,[1,4] with the most common isoform containing two immunoglobulin-like repeats and two fibronectin type III-like repeats in the extracellular region.[2] AXL is a member of the TYRO3/AXL/MERTK (TAM) family of RTKs, all of which bind to the growth arrest-specific protein 6 (GAS6) ligand. Of the three, GAS6 has the highest affinity for AXL. In normal cells, AXL activation begins with a 1:1 coordination of the AXL extracellular region with the GAS6 ligand.[5] Homodimerization of the AXL/GAS6 complex ensues to yield the final activated form (Fig. 1).[5] Activated AXL catalyzes tyrosine residue phosphorylation, thereby modulating several downstream signaling pathways, including PI3K/AKT/mTOR, MAPK, PKC, and JAK/STAT.[5,6] AXL biology is complex and ultimately beyond the scope of this article; however, the RTK has been implicated in various mechanisms, including growth, survival, inflammatory responses, DNA damage responses, angiogenesis, epithelial-to-mesenchymal transition (EMT), and cell proliferation.[2,5,7,8]

Figure 1.

Coordination, dimerization, and activation of AXL receptor tyrosine kinase. (1) Independent receptor and ligand. The transmembrane AXL receptor has not yet coordinated with the GAS6 ligand. In this state, AXL will not catalyze tyrosine residue phosphorylation. Therefore, AXL will not actively contribute to the regulation of downstream pathways. (2) AXL/GAS6 complex. Following a high-affinity coordination between the AXL receptor and GAS6 ligand, the AXL/GAS6 complex is now ready for homodimerization with another AXL/GAS6 complex. In this state, AXL will not catalyze tyrosine residue phosphorylation. (3) AXL dimer. After homodimerization, the AXL phosphorylation sites become active. In this state, AXL actively regulates downstream pathways and controls cellular processes. (Based on information from Tang et al.[4])

In malignant cells, AXL plays a key role in stemness, acquired therapeutic resistance, immunosuppression, survival, invasion, metastasis, and proliferation.[8] Overexpression of AXL has been observed in several cancers, including acute myeloid leukemia (AML), invasive breast cancer, non–small cell lung cancer (NSCLC), gastric adenocarcinoma, and colorectal adenocarcinoma.[9,10] Overexpression of AXL is correlated with resistance to tyrosine kinase inhibitors (TKIs) that target non-AXL receptors, such as the epithelial growth factor receptor (EGFR).[2,11,12] Although AXL typically homodimerizes, it is capable of heterodimerizing with structurally similar RTKs such as TYRO3, MERTK, EGFR, MET, PDGF, and HER2.[2,13] Heterodimerization may allow for ligand-independent autophosphorylation, allowing target RTKs to subvert inhibitors, resulting in drug resistance.[2,14] AXL has been implicated in drug resistance for patients with AML.[15] Melanoma patients with BRAF and NRAS mutations often display a phenotype of low MITF expression, high AXL expression, and high drug resistance.[16] Additionally, overexpression of AXL leads to upregulation of the aforementioned downstream signaling pathways. This upregulation enhances malignant cell growth and suppresses immune response.[2] Via the PI3K/AKT pathway, AXL/GAS6 interactions enhance the expression of Bcl-2, an anti-apoptotic protein.[15] Finally, EMT has been shown to increase AXL expression, and in turn, AXL enhances and sustains EMT via the upregulation of EMT transcription factors, thereby creating a positive feedback loop.[13]

Upregulation of AXL correlates with metastasis and worse prognosis.[17] A study of patients with renal cell carcinoma (RCC) demonstrated that AXL mRNA levels are an important independent prognostic factor for predicting patient survival. In this study (N = 221), participants with low AXL mRNA levels had a 70% chance of being alive at the end of the 307-month follow-up period, whereas patients with medium-high AXL mRNA levels had only a 25% chance of being alive at the end of the same follow-up period.[18] In addition, a study of patients with upper tract urothelial carcinoma reported similar findings but only for patients with a pathologic T stage (pT) of 2 or more.[19] A study of patients with pancreatic ductal adenocarcinoma reported that AXL expression correlated with lymph node metastases (p < 0.01) and shorter median survival (p < 0.01).[20] A study of patients with lung adenocarcinoma (n = 88), which measured the 5-year overall survival rate and AXL expression, reported that patients with low AXL expression had a 77.5% 5-year survival rate, in contrast to those with high AXL expression who had a 38.6% 5-year survival rate (p < 0.001).[21] The role of AXL as an independent prognostic factor makes it a potential therapeutic target.[13]

Empirical evidence from preclinical studies suggests that AXL inhibitors are an effective tool for controlling tumor growth. An in vitro study with AML cells found that AXL inhibitor SLC-391 abated the growth of cells with high AXL/GAS6 expression.[22] A xenograft study of YW327.6S2, a monoclonal antibody that blocks downstream AXL pathways by binding to AXL with high affinity, showed that treatment with YW327.6S2 could substantially reduce tumor growth in A549 NSCLC and MDA-MB-231 breast cancer models.[23] In an ectopic xenograft model treated with MAb173, a monoclonal antibody that degrades AXL receptors, nude mice were implanted with either KS-SLK or LTC cell lines and then treated with either MAb173 or an immunoglobulin control. After 20 days, mice in the KS-SLK+MAb173 group saw an average tumor volume reduction to 50% of the initial volume, in contrast to mice implanted with the KS-SLK cell line and treated with an immunoglobulin control, in which average tumor volume increased to 417% of the initial volume. Mice in the LTC+MAb173 group experienced a 50% reduction in tumor volume after 7 days.[24]

Inspired by the independent prognostic role of AXL and the impressive efficacy of AXL inhibitors in preclinical studies, this narrative review aimed to provide a concise and comprehensive summary of AXL inhibitors, including both published clinical trial results (Table 1) and those without (Table 2). [25–65,73–80] The clinical trial results presented in this review were obtained from peer-reviewed abstracts presented at oncology conferences, peer-reviewed publications, and information posted on ClinicalTrials.gov; the search was completed on August 15, 2024. The drugs covered in this review fall under various classes, including antibody drug-conjugates (ADCs), monoclonal antibodies, TKIs, and GAS6-targeting soluble receptors.

Table 1.

Clinical trials of selective AXL inhibitors with published results

Drug Name	Trial Phase	Tumor Types	MTD/RP2D	Dose-Limiting Toxicities	Number of Patients	Terminal Half-Life	Antitumor Efficacy	Examined Biomarkers
Batiraxcept[25]	1	N/A	10 mg/kg	N/A	42	N/A	N/A	N/A
Batiraxcept with avelumab[27]	1b	mUC	N/A	G3 fatigue	15	N/A	38% ORR (of 13); 1 SD; treatment without disease progression >6 mo (n = 3) of 7, 19, and 21 mo	AXL expression, GAS6 expression PD-L1 expression
Batiraxcept with cabozantinib[31]	1b/2	ccRCC	15 mg/kg	No DLT	51	N/A	43.1% ORR, mPFS 9.2 mo. In patients with prior VEGF TKI treatment 53.8% ORR, mPFS 11.4 mo.	N/A
Batiraxcept with cabozantinib and nivoluma[30]	2	ccRCC	15mg/kg	N/A	46	N/A	Batiraxcept + cabozantinib 36% ORR (PR+CR), mPFS 7.2 mo, clinical benefit rate (ORR+SD) 72% Batiraxcept+ Nivolumab 55% ORR (PR+CR), mPFS 7.6 mon, Clinical benefit rate 64%	Serum soluble AXL/GAS6
Batiraxcept and durvalumab[28]	1b	PROC	15 mg/kg	No DLT	11	N/A	1 SD (3 mo)	GAS6 expression
Batiraxcept with gemcitabine and nab-paclitaxel[29]	1b	PDAC	15mg/kg	N/A	21	N/A	29% ORR, mPFS 5.4 mo.; mOS 12.3 mo, >MEC OS 8.5 mo	Serum GAS6 expression
Batiraxcept/placebo with paclitaxel[32]	3	PROC	15 mg/kg	N/A	366	N/A	Batiraxcept + paclitaxel: ORR 25.1%, mPFS 5.13 mo, mOS 14.29 mo In (n = 304) AXL expressing tumors Batiraxcept + paclitaxel: mPFS 5.78 mo, mOS 17.8 mo	AXL expression
Batiraxcept with paclitaxel and pegylated liposomal doxorubicin[26]	1b	PROC	15 mg/kg	No DLT	53	N/A	PAC + AVB-500 34.8% ORR + 2 CR, DoR –> 7mo ––––––––––––– PLD + AVB-500 10.7% ORR + DoR –> 4.2 mo.	Serum GAS6
Bemcentinib[34]	1	AML and myelodyplastic neoplasms	N/A	QTc prolongation	25	N/A	1 CRi, 3 PR, 4 SD	Phosphorylated AXL, Phosphorylated Erk/MapK, Phosphorylated Akt, Soluble AXL, Osteopontin, TCRß repertoire
Bemcentinib[35]	2	AML and myelodysplastic neoplasms	N/A	N/A	45	N/A	1 CR, 5 mCR, 1 PR, 4 SD	STAG 2
Bemcentinib with cytarabine[36,37]	1b/2	Relapsed and refractory acute myeloid leukemia	200 mg/day	N/A	27	N/A	4 CR/CRi and 4 SD	Longitudinal plasma, bone marrow samples,TNF-alpha pathway activation and IFN-gamma pathway activation in CD8+ T-cells, B plasma cell activation, general immune compartment changes
Bemcentinib with dabrafenib+ trametinib or pembrolizumab[39]	1b/2	Metastatic melanoma	200 mg/day	G3 rash	23	N/A	N/A	Plasma protein
Bemcentinib with docetaxel[38]	1	NSCLC	60 mg/m2	G4 neutropenia	21	N/A	6 PR, 8 SD	Plasma protein
Bemcentinib with pembrolizumab[41]	2	Adenocarcinoma	200 mg/day	N/A	66	N/A	1 PR	cAXL score, PD-L1 TPS, genome-wide mutational analysis, transcriptome analysis
DS-1205c with gefitinib[43]	1	EGFR-mutated NSCLC	800 mg BID	Grade-3 neutropenia, grade-3 nausea	20	N/A	5 (25%) SD	Interleukin-8 sAXL
DS-1205c with osimertinib[44]	1	EGFR-mutated, NSCLC	N/A	Grade 3 pneumonia, increased ALT	13	N/A	69.2% SD	AXL expression
Dubermatinib[46,47]	1a/b	Advanced solid tumors, EGFRmut NSCLC, KRASmut CRC, platinum- resistant ovarian, BRAFmut/wt melanoma	50 mg/day	G4 thrombocytopenia	164	20 hr	4 PR, 19 SD (of 125)	EGFR, KRAS, BRAF, sAXL, GAS6
Dubermatinib with decitabine[48,49]	1b/2	AML	25 mg/day	N/A	27	N/A	4 CR, 4 CRh, 2 CRi; 6 MRD	TP53m, sAXL, GAS6
Enapotamab vedotin[52]	1	NSCLC, melanoma, ovarian, cervical, endometrial	2.2 mg/kg Q3W	constipation, vomiting, γ-glutamyltransferase increase, febrile neutropenia, diarrhea	47	2.2 d	3 PR	N/A
Enapotamab vedotin[53]	2a	NSCLC	N/A	N/A	26	N/A	19% ORR, 50% CR+PR+SD	AXL, EGFR WT, ALK-
FC084CSA[54]	1	Advanced solid tumors	N/A	No DLT	9	N/A	(62.5%) Disease control rate	N/A
Mecbotamab vedotin[58]	1	Advanced solid tumors	N/A	N/A	67	4 days	N/A	N/A
Mecbotamab vedotin with nivolumab[59]	2a	Advanced refractory sarcoma	N/A	N/A	113/300	N/A	3 PR	AXL expression
Mecbotamab vedotin with nivolumab[60]	2	Non-squamous NSCLC	N/A	N/A	40	N/A	1 CR, 2 PR, 8 SD	N/A
Tamnorzatinib with nivolumab[61]	1	Advanced or metastatic solid tumors	N/A	G4 nephritis, G3 colitis, G3 hepatic function abnormal	12	N/A	8.3% ORR, 8.3% PR, 25% SD	T-cell number, inflammatory (Ma) macrophages to immunosuppressive (M2) ratio
Tamnorzatinib with venetoclax[62,63]	1/2	AML, myelodysplastic syndromes	N/A	No DLT	42	N/A	Part D 1 CRi, 2 PR	N/A
Tilvestamab[65]	1	PROC	N/A	No DLT	16	N/A	5 SD	N/A

AML: acute myeloid leukemia; BID: twice daily; ccRCC: clear cell renal cell carcinoma; CR: complete response; CRC: colorectal cancer; CRh: complete remission with partial hematologic recovery; CRi: complete remission with incomplete count recovery; DLT: dose-limiting toxicities; DoR: duration of response; mCR: morphologic complete remission; GAS6: growth arrest-specific protein 6; MEC: minimally efficacious concentration; mOS: median overall survival; mPFS: median progression-free survival; MRD: minimal residual disease; mUC: metastatic urothelial carcinoma; N/A: not available; NSCLC: non-small cell lung cancer; ORR: objective response rate; OS: overall survival; PDAC: pancreatic ductal adenocarcinoma; PROC: platinum-resistant ovarian cancer; PR: partial response; SD: stable disease; TNF-alpha: tumor necrosis factor-alpha; TKI: tyrosine kinase inhibitors; TPS: tumor proportion score; VEGF: vascular epithelial growth factor.

Table 2.

Ongoing clinical trials of AXL inhibitors without published results

AXL Inhibitor	Monotherapy/Combination	Trial Phase	Tumor Type	Trial NCT Identifier	Study Start Datea	Projected Study Completion Datea
Bemcentinib[73]	Monotherapy/combination (pembrolizumab)	2a	Malignant mesothelioma	NCT03654833	01/28/2019	10/31/2023
FC084CSA[74]	Combination with tislelizumab	1b/2a	Advanced malignant solid tumors	NCT06499350	09/10/2024	09/01/2026
INCB081776[75]	Monotherapy/combination (INCMGA00012)	1a/1b	Advanced malignancies in solid tumors	NCT03522142	08/27/2018	12/31/2024
INCB081776[76]	Combination with pembrolizumab and palliative radiotherapy	1	Head and neck squamous cell carcinoma	NCT06308913	10/01/2024	08/31/2027
NTQ2494[77]	Monotherapy	1	AML, advanced hematological malignancies	NCT06049667	08/07/2023	08/2026
PF-07265807[78]	Monotherapy/combination (sesanlimab, axitinib)	1	Selected advanced or metastatic solid tumors	NCT04458259	09/24/2020	06/30/2024
XZB-0004[79]	Monotherapy	1a/1b	AML, MDS	NCT05740917	02/2023	02/2023
XZB-0004[80]	Monotherapy/ combination (peamplimab)	1	NSCLC, advanced solid tumors	NCT05772455	04/2023	02/2027

^aDates are presented as Month/Day/Year.

AML: acute myeloid leukemia; MDS: myelodysplastic syndrome; NSCLC: non-small cell lung cancer.

BATIRAXCEPT

Batiraxcept (AVB-500, AVB-S6-500; Aravive, Inc., Houston, TX) is a high-affinity Fc-sAXL fusion protein intended to emulate membrane-bound AXL. As such, Batiraxcept binds to serum GAS6, competitively inhibiting interactions with membrane-bound AXL receptors. The interaction reduces the ability of free GAS6 to bind with endogenous AXL, potentially inhibiting the downstream signaling associated with cancer progression.[25] The first-in-human phase 1 trial of batiraxcept was performed in healthy volunteers, not patients with cancer. A total of 42 healthy volunteers were dosed in five cohorts with single increasing doses of 1, 2.5, 5, and 10 mg/kg intravenously (IV), and a repeat dose cohort receiving 5 mg/kg weekly for 4 weeks. No serious adverse events were reported, and batiraxcept was well tolerated across all doses. Serum GAS6 levels, measured using Aravive’s proprietary pharmacodynamic (PD) assay, were suppressed for 22 days at the 5-mg/kg dose level and 29 days at the 10-mg/kg dose level, following single doses. Although not clarified by Aravive, the proprietary assay appears to be epitope sensitive, detecting only unbound GAS6. As such, batiraxcept’s mechanism of action would explain the reported suppression in serum GAS6. Weekly 5-mg/kg doses suppressed sGAS6 in four of six subjects for at least 3 weeks after the fourth dose. Preclinical pharmacokinetic and pharmacodynamic modeling using phase 1 data from healthy volunteers, along with simulations of increased sGAS6 levels, indicated that dosing regimens of 5 mg/kg weekly or 10 mg/kg every other week would effectively reduce sGAS6 levels in patients with cancer. Based on these data, the recommended phase 2 dose (RP2D) was 10 mg/kg every other week for the phase 1b trial in platinum-resistant recurrent ovarian cancer.[25]

A phase 1b trial combined batiraxcept with paclitaxel or pegylated liposomal doxorubicin for patients with platinum-resistant ovarian cancer.[26] Batiraxcept was administered intravenously once every 2 weeks (Q2W) in doses of 10, 15, or 20 mg/kg in combination with paclitaxel 80 mg/m² on days 1, 8, and 15 of a 28-day cycle. The pegylated liposomal doxorubicin was given 40 mg/m² on day 1 of a 28-day cycle. A total of 53 patients were treated, including 23 patients on the paclitaxel combination and 30 patients on the doxorubicin combination. The more common adverse effects observed included fatigue (30.4% paclitaxel, 16.7% doxorubicin), infusion reactions (21.7% paclitaxel, 20.0% doxorubicin), anemia (21.7% paclitaxel, 6.7% doxorubicin), and nausea (13.0% paclitaxel, 13.3% doxorubicin). No dose-limiting toxicities (DLTs) were identified. The RP2D of batiraxcept in this combination was 15 mg/kg. Target-mediated drug disposition was evident in the pharmacokinetic analysis, which was verified by a model of informed drug development method that helped identify the RP2D. In the combination arm with paclitaxel, the objective response rate (ORR) was 34.8%, including two complete responses (CRs), with a median duration of response of 7.0 months, median progression-free survival (mPFS) of 3.1 months, and median overall survival (mOS) of 10.3 months. The greatest efficacy was observed in patients with no previous bevacizumab and batiraxcept trough levels greater than 13.8 mg/L, with ORR 50% or more, mOS 19 months or longer, and mPFS 7.5 months or longer. In the combination arm with pegylated liposomal doxorubicin, the ORR was 10.7%, with a median duration of response of 4.2 months, mPFS of 3.61 months, and mOS of 11.2 months.[26]

Because of the promising results demonstrated in the phase 1b study of the combination of batiraxcept and paclitaxel in ovarian cancer, a placebo-controlled, double-blind randomized phase 3 trial of this combination was launched in patients with platinum-resistant ovarian cancer (PROC). A total of 366 patients were randomly assigned 1:1 to either receive a combination of batiraxcept (IV, 15 mg/kg, Q2W) + paclitaxel (IV, QW) or placebo + paclitaxel.[27] Study arm assignment was stratified based on prior lines of therapy (1–4), bevacizumab treatment status, and platinum-free interval (<3 months, 3–6 months). Of the total patients enrolled, 183 had received prior bevacizumab treatment. The batiraxcept + paclitaxel arm had an ORR of 25.1%, and the control arm had an ORR of 26.2%. The mPFS of the batiraxcept + paclitaxel combination was 5.13 months versus 5.49 months in the placebo + paclitaxel arm. The mOS of the batiraxcept and paclitaxel arm was 14.29 months compared with 14.39 months in the placebo + paclitaxel arm. Additional analysis of 304 tumors revealed 20% overexpressed AXL. Patients with AXL tumor overexpression achieved an mPFS of 5.78 months with batriaxcept + paclitaxel versus an mPFS of 3.71 months with placebo + paclitaxel. The mOS of patients with tumors that overexpressed AXL was 17.8 months with batiraxcept + paclitaxel and 8.11 months with placebo + paclitaxel. Therefore, in patients with AXL tumor overexpression, the combination of batiraxcept + paclitaxel achieved a higher mPFS and mOS than in the treatment of paclitaxel alone.[27]

In a phase 1b open-label dose escalation trial, the efficacy and tolerability of the combination of batiraxcept with durvalumab were evaluated.[28] Patients (n = 11) with platinum-resistant ovarian cancer and a median of three prior lines of therapy received durvalumab (1500 mg Q4W) and batiraxcept at concentrations of 10, 15, or 20 mg/kg Q2W IV. No DLTs were reported. The most common adverse event observed was elevated liver enzymes (36%). One patient achieved stable disease (SD) for 3 months. Elevated serum AXL levels (102 and 112 ng/mL) were observed in two patients. Pharmacodynamic and pharmacokinetic analysis of batiraxcept demonstrated expected concentrations on cycle 1 day 1 postdose but lower than expected levels at cycle 2 day 1 postdose. This combination was well tolerated in patients at all dose levels.[28]

In a phase Ib study of urothelial carcinoma patients, IV batiraxcept was administered at doses of 5 mg/kg weekly, 10 mg/kg every 2 weeks, 15 mg/kg every 2 weeks, or 20 mg/kg every 2 weeks, in combination with avelumab (an anti-programmed death ligand-1 [PD-L1] antibody) 800 mg every 2 weeks. Fifteen patients with PD-1/L1-inhibitor naive metastatic urothelial carcinoma who were ineligible for chemotherapy treatment were enrolled.[29] Treatment-related adverse events (TRAEs) grade 3 or higher were observed in six patients, including urinary tract infection (n = 3), hyponatremia (n = 1), elevated creatinine (n = 1), and a combination of anemia, thrombocytopenia, hematuria, anorexia, and sepsis in one patient. One patient experienced a DLT of grade 3 fatigue at the 10 mg/kg every 2-weeks dose level. The maximum tolerated dose (MTD) was not reached. Pharmacokinetic studies showed that in 85% of patients, circulating GAS6 levels were effectively suppressed from a median of 28.4 ng/mL to below the detection threshold. The ORR rate was 38%, with one patient achieving SD. Durable responses lasting more than 6 months were seen in three patients (7, 19, and 21 months). Batiraxcept successfully neutralized circulating GAS6 across dose levels.[29]

A phase 2 trial combining batiraxcept with cabozantinib and nivolumab was performed in patients with clear cell renal cell carcinoma (ccRCC).[30] This trial administered batiraxcept at 15 mg/kg IV every 2 weeks. The first cohort included batiraxcept as monotherapy (n = 10) in patients with relapsing disease without curative treatment available. The second cohort was batiraxcept in combination with cabozantinib 60 mg orally daily (n = 25) in patients who had received at least one prior line of therapy. The third cohort was batiraxcept in combination with cabozantinib 40 mg orally daily and nivolumab 240 mg Q2W or 480 mg Q4W in the first-line setting (n = 11). A total of 46 patients were treated. The authors reported that batiraxcept monotherapy was well tolerated but demonstrated limited efficacy. In contrast, the combination of batiraxcept with cabozantinib demonstrated encouraging efficacy, which the authors did not explicitly describe in the abstract. Because of the promising early efficacy, the authors indicated plans for further investigation of the combination in a phase 3 trial of ccRCC patients who have received at least one prior line of therapy, including progressive disease on prior immunotherapy or vascular endothelial growth factor (VEGF) TKI treatment. An ongoing analysis of baseline serum soluble AXL/GAS6 ratio in this study will assess this biomarker for potential predictive value.[30]

Because increased expression of AXL is caused by hypoxia-induced factor 1a expression in ccRCC, a phase 1b/2 trial combining batiraxcept with cabozantinib was performed in patients with advanced ccRCC.[31] Overexpression of AXL has been associated with the development of resistance against VEGF inhibitors and the control of the innate immune response by preventing inflammation mediated by macrophages. In this trial, batiraxcept was administered IV Q2W, at doses of 15, 20, and 25 mg/kg, in combination with cabozantinib 60 mg oral daily. The study included 51 patients (ages 40–81 years), with advanced ccRCC, who received at least one prior systemic therapy. No DLTs were observed. TRAEs occurred in 17 (84%) of patients. The most common adverse events included diarrhea (31%), fatigue (31%), and infusion-related reactions (24%); 10% of patients discontinued batiraxcept due to adverse events. The ORR was 43.1% for the entire cohort, with a mPFS of 9.2 months. In patients with prior VEGF TKI treatment, the ORR was 53.8%, and the mPFS was 11.4 months.[31]

In a phase 1b dose escalation study, the efficacy and tolerability of the combination of batiraxcept, gemcitabine, and nab-paclitaxel as a first-line treatment was evaluated in patients with advanced pancreatic adenocarcinoma (PDAC).[32] Patients received batiraxcept at 15 mg/kg on days 1 and 15, together with gemcitabine 1000 mg/m² and nab-paclitaxel 125 mg/m² on days 1, 8, and 15 of the 28 day cycle. Twenty-one patients were treated, including 14% who had received prior therapy. TRAEs included fatigue (33%), diarrhea (19%), and neutropenia (14%). The median duration of treatment was 12.3 months, ORR was 29%, mPFS was 5.4 months, and mOS was 12.3 months. The minimally efficacious concentration (MEC) of 14.5 mg/L of batiraxcept was deduced. Efficacy data were reported in patients who received a dose of batiraxcept larger or smaller than the MEC. Among the nine patients who received a dose higher than the MEC, five achieved partial response (PR), two achieved SD, and the mPFS was 5.6 months. In contrast, of the nine patients who received a dose lower than the MEC, one CR was observed, two patients achieved SD, four patients had progressive disease, and mPFS was 2.7 months. Overall, patients who received a dose concentration larger than the MEC had a higher mPFS and mOS rate.[32]

BEMCENTINIB

Bemcentinib (BGB324; Rigel Pharmaceuticals, Inc., San Francisco, CA) is a selective kinase inhibitor that binds to and obstructs the activity of AXL, an intracellular catalytic kinase domain. Upon its binding to the receptor AXL, it inhibits EMT through signal transduction pathways, thereby reducing tumor proliferation and migration.[33] Administration of bemcentinib correlated with the modulation of proteins involved in several processes, such as protein kinase B signaling and reactive oxygen species metabolism. A phase 1 trial evaluated the safety and efficacy of bemcentinib as monotherapy in patients with relapsed and refractory AML and myelodysplastic syndrome (MDS). Bemcentinib was administered orally at three dose levels (loading dose days 1–2/maintenance dose): 400 mg/100 mg, 600 mg/200 mg, and 900 mg/300 mg. Twenty-five patients were treated, including 21 with AML and four with MDS. The most commonly observed adverse events were diarrhea and fatigue, mostly grades 1 and 2. A DLT of QTc prolongation was observed, while the MTD had not yet been determined. Of the 25 patients enrolled, one achieved complete remission with incomplete count recovery (CRi), three achieved PR, and four achieved SD.[34]

Owing to promising results, a phase 2 trial evaluated the effectiveness of bemcentinib in patients with AML or higher-risk myelodysplastic neoplasms.[35] Bemcentinib was orally administered once a day at a dosage of 400 mg for the first 3 days of cycle 1 as a loading dose and 200 mg for all following days of treatment as a maintenance dose. Forty-five patients (MDS = 18, AML = 27) were treated on this trial and received at least one cycle of bemcentinib. The patients had a median age of 79 years, with ages ranging from 62–86 years. Only 16 patients (MDS = 11, AML = 5) were able to complete the primary four cycles of treatment. Treatment discontinuation of other patients was due to disease progression, disease-related death, and withdrawal of consent. Within the MDS cohort, eight of 18 patients responded, with one CR, five marrow CRs, one PR, and one SD. Within the AML cohort, bemcentinib was observed to have a less pronounced effect, with only three SDs observed. The observed grade 4 TRAEs included neutropenia (n = 2) and C-reactive protein increase (n = 1). Grade 3 TRAEs included QT prolongation (n = 3), anemia (n = 1), thrombocytopenia (n = 1), diarrhea (n = 1), asthenia (n = 1), lactate dehydrogenase (LDH) increase (n = 1), and decreased appetite (n = 1). In the three patients with QT prolongation, the drug was stopped for one patient, followed by normalization of the QT, and in the other two patients, no action was taken. Bemcentinib-related serious adverse events were observed in 14 of 45 (31%) patients. Grade 5 events included kidney injury (n = 1) and disease progression (n = 2). Fourteen grade 3 events were observed in 12 patients, which included sepsis (two events observed in one patient), pneumonia (n = 1), acute kidney injury (n = 1), periodontitis (n = 1), febrile neutropenia (n = 1), upper gastrointestinal hemorrhage (n = 1), pneumonitis (n = 1), abdominal pain (n = 1), nausea (n = 1), febrile bone marrow aplasia (n = 1), bone pain (n = 1), general physical health deterioration (n = 1), and headache (n = 1).[35]

A phase 2 trial evaluated bemcentinib in combination with low-dose cytarabine in patients with relapsed and refractory AML.[36] Bemcentinib was orally administered daily at 200 mg, with cytarabine 20 mg subcutaneously twice daily for 10 days every 28 days.[37] Twenty-seven patients with AML were treated, including 20 with relapsed disease and seven with refractory disease. Of the 20 relapsed patients, 17 were evaluable for efficacy, and of these patients, 4 experienced a CR and 4 experienced SD. Of the seven refractory patients, none achieved a response. The only observed TRAEs of grade 3 and above in greater than 10% of patients included anemia and QT prolongation.[36]

A phase 1 dose escalation and expansion study of bemcentinib in combination with docetaxel enrolled patients into two cohorts. In the first cohort, a loading dose of 200 mg of bemcentinib was administered by mouth for the first 3 days of treatment, followed by 100 mg daily.[38] In the second cohort, a loading dose of 400 mg of bemcentinib was administered by mouth for the first 3 days, followed by 200 mg daily. In both cohorts, a standard dose of 60 or 75 mg/m² of docetaxel was administered IV Q3W. Monotherapy of bemcentinib was given 1 week before the beginning of docetaxel treatment to evaluate pharmacodynamic and pharmacokinetic effects. Prophylactic granulocyte colony-stimulating factor was added upon observation of hematologic toxicity.[38] A total of 21 patients with NSCLC were enrolled, including 76% with lung adenocarcinoma and a median of two prior lines of therapy. The most commonly observed TRAEs included neutropenia (86%), diarrhea (57%), fatigue (57%), nausea (52%), neuropathy (43%), alopecia (38%), edema (38%), neutropenic fever (38%), and myalgia (33%). The only TRAEs grade 3 or above were neutropenia (76%), neutropenic fever (38%), leukopenia (29%), fatigue (5%), neuropathy (5%), hyponatremia (5%), mucositis (5%), QTc prolongation (5%), and rash (5%). Four DLTs were observed, all due to grade 4 neutropenia lasting 1 week or longer. The MTD was 60 mg/m² of docetaxel with prophylactic granulocyte colony-stimulating factor support and 400 mg of bemcentinib for the first 3 days and 200 mg daily thereafter. Samples for pharmacokinetics analysis were available for 13 patients. The geometric mean plasma trough concentration of bemcentinib ranged from 47 to 53 ng/mL between C1D1 and C4D1. At steady state, the mean AUC over 24 hours was 2824 ± 420 ng · h/mL, similar to the monotherapy values for bemcentinib (3100 ± 1370 ng·h/mL). Of the 17 evaluable patients, 35% had PRs and 47% experienced SD.[38]

An open-label phase 1b/2 trial observed the effects of bemcentinib in combination with either dabrafenib+trametinib (D+T) or pembrolizumab in patients with metastatic melanoma.[39] In part one of the trial, patients received pembrolizumab at 2 mg/kg IV every 3 weeks (Q3W) and 200-mg bemcentinib capsules once daily. Patients on the combination arm with D+T orally took 100 or 200 mg capsules of bemcentinib daily, 150 mg dabrafenib capsules twice daily, and 2 mg of trametinib once daily.[40] In part one, six patients were enrolled, in which one DLT was observed (grade 3 rash). A RP2D of 200 mg of bemcentinib daily with a full dose of D+T was found. In part two, patients were enrolled in a ratio of 2:1 to receive either bemcentinib with D+T or bemcentinib with pembrolizumab at the RP2D. Seventeen patients were enrolled in part two of the trial, in which grade 3 TRAEs were observed in seven (30%) patients. Efficacy results from part two are not yet available.[39]

A single-arm, phase 2 trial orally administered 200 mg of bemcentinib daily in combination with 200 mg of pembrolizumab Q3W IV for previously treated stage 4 lung adenocarcinoma patients.[41] Patients were enrolled into one of three cohorts defined as follows: cohort A included chemotherapy-pretreated immunotherapy-naïve patients, cohort B included patients progressing on immunotherapy, and cohort C included patient receiving chemotherapy and pembrolizumab combination. In stage 1, 66 patients with NSCLC were enrolled in cohorts A (n = 50) and B (n = 16). The most common TEAEs included elevated ALT (29%), elevated AST (29%), and diarrhea (29%). Among the 16 patients in cohort B, 15 were radiologically evaluable, including one patient who achieved a PR.[41]

DS-1205c

DS-1205c (AB-329; Daiichi Sankyo, Inc., Japan) is a specific, orally available small-molecule AXL TKI. DS-1205c inhibits AXL activation and AXL-mediated signal transduction pathways.[42] In preclinical studies, DS-1205c has shown the ability to reverse resistance to EGFR-directed treatment. To date, two clinical trials of DS-1205c have opened. The first-in-human open-label, multicenter phase I study investigated the efficacy of the combination of DS-1205c and gefitinib in Japanese patients.[43] The included patients were primarily women (80%), with a median age of 68.5 years. Patients (n = 20) enrolled in the study were diagnosed with metastatic or unresectable EGFR-mutant NSCLC. DS-1205c was administered as monotherapy for a lead-in, safety monitoring cycle of 7 days, followed by combination with gefitinib in subsequent 21-day cycles. DS-1205c was given orally twice a day (BID) at concentrations of 200, 400, 800, 1000 or 1200 mg, and gefitinib was given orally at 250 mg once a day. The most common treatment-emergent adverse events (TEAEs) were an increase of aspartate aminotransferase (35%), an increase of alanine aminotransferase (30%), maculopapular rash (30%), and diarrhea (25%). The TEAEs observed were classified as nonserious. Two DLTs of grade 3 neutropenia (800 mg BID) and grade 3 nausea (1200 mg BID) were identified. Five patients (25%) achieved SD, 14 patients (70%) showed disease progression, and no patients achieved CR or PR. Although DS-1205c was reported to be safe throughout the 200–1200-mg dose range, the dose concentration of less than 800 mg BID was more optimal for safety than 1200 mg BID. The optimal recommended dose of combination therapy of DS-1205c with gefitinib was 800 mg BID for dose-expansion cohorts.[43]

The second study was a phase I, open-label, nonrandomized study in Taiwan, which investigated the safety and efficacy of combination DS-1205c and osimertinib.[44] Patients enrolled in the study (n = 13) were diagnosed with metastatic or unresectable EGFR-mutant NSCLC and experienced tumor progression and resistance to prior EGFR TKI treatment. DS-1205c was administered orally two times a day as monotherapy in concentrations of 200, 400, 800, or 1200 mg for a lead-in cycle of 7 days. DS-1205c was combined with osimertinib for subsequent 21-day cycles. For the combination therapy stage, the concentration of DS-1205c remained unchanged, and osimertinib was given orally once per day at 80 mg. Median number of cycles was five, and the median number of days of treatment was 90 days. All patients experienced at least one TEAE. The most common TRAEs were anemia, diarrhea, fatigue, increased AST and ALT, increased blood creatinine phosphokinase, and increased lipase levels. All TRAEs were classified as nonserious except for an overdose of osimertinib in one patient. One patient treated at a dose of 200 mg developed a DLT of grade 3 pneumonia. No patients achieved CR or PR, three demonstrated progressive disease, and nine were observed to have SD. No deaths were documented. No new safety concerns were identified in this combination, which was determined to be safe and tolerable.[44]

DUBERMATINIB

Dubermatinib (TP-0903; Sumitomo Pharma, Osaka, Japan) is a kinase inhibitor that binds AXL, blocking AXL/GAS6 interactions, thereby preventing AXL activation and blocking the regulation of downstream signaling pathways.[45] Administered orally, dubermatinib has completed phase 1a/b and phase 1b/2 studies. During the first-in-human phase 1 dose-escalation study, 45 patients with advanced solid tumors enrolled in 9 cohorts at various dose levels, including 1.5 to 37 mg/m² or a 50-mg flat dose.[46] Patients were dosed daily on days 1–21 of a 28-day cycle. Grade 3 or higher adverse events included thrombocytopenia, syncope, anemia, vomiting, and nausea. One DLT of grade 4 thrombocytopenia was observed at 28 mg/m² daily (QD).[47] Pharmacokinetics were determined to be dose proportionate. The RP2D was determined to be 50 mg/day.[46]

An expansion of this study enrolled five additional cohorts.[46] The cohorts were: (1) dubermatinib + immunotherapy combination for patients who previously responded to immunotherapy and then progressed (n = 19); (2) dubermatinib + EGFR TKI combination for patients with EGFR-mutated NSCLC who previously responded to an EGFR TKI and then progressed (n = 18); (3) dubermatinib monotherapy for patients with KRAS-mutated colorectal cancer (n = 47); (4) dubermatinib monotherapy for patients with platinum-resistant ovarian cancer (n = 22); and (5) dubermatinib monotherapy for patients with BRAF^mut/wt melanoma (n = 13). Results were reported collectively for all patients who received at least one 50-mg dose, regardless of whether it was given alone or in combination. Of the 125 patients who received at least one 50-mg dose, the most common grade 3 or higher adverse events were anemia (n = 7), diarrhea (n = 7), hyponatremia (n = 5), dyspnea (n = 5), vomiting (n = 3), ascites (n = 3), fatigue (n = 3), increased alkaline phosphatase (n = 3), hypokalemia (n = 3), and pulmonary embolism (n = 3). The half-life of dubermatinib was 12–20 hours. After a patient’s first 50-mg dose, the maximum concentration (C_max) was 14.8 ng/mL. The area under the curve for the first 24 hours after the 50-mg dose (AUC_0-24) was 160.9 ng·hr/mL. Of the 125 patients who received at least one 50-mg dose, four patients had PR, including one patient with NSCLC who was treated with dubermatinib + EGFR TKI, one patient with NSCLC who was treated with dubermatinib + nivolumab, one patient with melanoma who was treated with dubermatinib monotherapy, and one patient with cholangiocarcinoma who was treated with dubermatinib monotherapy. The overall clinical benefit rate (CR/PR/SD > 4 months) was 18.4%.[46]

A phase 1b/2 combination study of dubermatinib with decitabine enrolled 27 patients newly diagnosed with AML older than 60 years of age. All patients had a TP53 mutation and/or a complex karyotype, both of which are associated with poor prognosis. Patients were dosed on a 28-day cycle, receiving dubermatinib (25–37 mg/day) on days 1–21 and decitabine (20 mg/m²) on days 1–10. Fifteen patients were dosed with 37 mg/day of dubermatinib before concerns about delayed cytopenia recovery warranted a dose reduction to 25 mg/day for the remaining 12 patients.[48] For patients in both the 37- and 25-mg/day groups, grade 3 or higher TRAEs were largely hematologic. In the 37-mg/day group, 33.3% experienced neutropenia, 26.7% thrombocytopenia, 20% leukopenia, and 13.3% anemia. In the 25-mg/day group, 50% experienced neutropenia, 41.7% lymphopenia, 33.3% febrile neutropenia, 33.3% leukopenia, and 25% thrombocytopenia. In combination with decitabine, the RP2D for dubermatinib was 25 mg/day. Of the 15 patients dosed at 37 mg/day, three achieved CRh and two achieved CR, for a CR/CRh/CRi rate of 33.3%. Of the 12 patients dosed at 25 mg/day, two achieved CRi, one achieved complete remission with partial hematologic recovery (CRh), and three achieved CR, for a CR/CRh/CRi rate of 50%. Four patients in the 37 mg/day group and two patients in the 25 mg/day group achieved minimal residual disease–negative status.[49]

ENAPOTAMAB VEDOTIN

Enapotamab vedotin (EnaV, HuMax-AXL-ADC; Genmab, Copenhagen, Denmark) is an AXL-targeting ADC. EnaV binds to the AXL immunoglobulin-like region before entering the cell via receptor-mediated endocytosis. The ADC then releases monomethyl auristatin E (vedotin),[50] disrupting the polymerization of tubulin and preventing mitosis.[51] Administered via IV, EnaV completed a first-in-human phase I dose-escalation trial with doses ranging from 0.3–2.8 mg/kg Q3W and from 0.45–1.4 mg/kg 3Q4W.[52] The phase I dose-escalation study enrolled 47 patients: eight with NSCLC, nine with melanoma, 22 with ovarian cancer, three with cervical cancer, and five with endometrial cancer. Common adverse events included diarrhea (47%), constipation (57%), nausea (57%), and fatigue (64%). There were six DLTs, including constipation (2.0 mg/kg Q3W and 2.2 mg/kg Q3W), vomiting (2.2 mg/kg Q3W), γ-glutamyl transferase increase (2.4 mg/kg Q3W), febrile neutropenia (1.2 mg/kg 3Q4W), and diarrhea (1.2 mg/kg 3Q4W). Two MTDs were determined and included 2.2 mg/kg Q3W and 1.0 mg/kg 3Q4W. The RP2D was 2.2 mg/kg Q3W. The median half-life of EnaV was in the range of 0.9–2.2 days. Of the 47 patients, three had PR: one with NSCLC 2.2 mg/kg Q3W, one with ovarian 1.5 mg/kg Q3W, and one with ovarian 2.4 mg/kg Q3W.[52]

The phase 2a expansion trial enrolled 26 patients with NSCLC with no sensitizing EGFR mutations and no ALK rearrangements.[53] All patients had failed at least four lines of prior therapy. Patients were dosed via IV with the RP2D (2.2 mg/kg IV Q3W). Preliminary results reported that 12 of the 26 patients had grade 3 or higher TEAEs. Many of these were gastrointestinal adverse events, such as constipation (n = 1), colitis (n = 2), diarrhea (n = 2), nausea (n = 2), vomiting (n = 2), and abdominal distension (n = 1). The overall response rate was 19%, and the disease control rate was 50%.[53]

FC084CSA

FC084CSA (FindCure Biosciences (ZhongShan) Co., Ltd, Beijing, China) is a highly selective AXL kinase inhibitor. The first in-human phase 1 study evaluated the efficacy and tolerability of FC084CSA monotherapy in patients with advanced solid tumors.[54] As of Oct 1, 2024, nine patients (age range: 44–73 years) received FC084CSA orally at concentrations of 100, 200, 400, and 600 mg once daily. Eight patients experienced TRAEs, which included increased blood lactate dehydrogenase (44.4%), increased γ-glutamyl transferase (33.3%), proteinuria (33.3%), and anemia (33.3%). One grade 3 TRAE was observed. No DLTs were reported. An ORR of 0% and a disease control rate of 62.5% were observed in the eight patients who had undergone at least one post-baseline tumor assessment.[54]

MECBOTAMAB VEDOTIN

Mecbotamab vedotin (BA3011; BioAtla, Inc., San Diego, CA) is an ADC designed to target the receptor tyrosine kinase AXL conditionally and reversibly.[55] Mecbotamab is comprised of a conditionally active biologic antibody conjugated to monomethyl auristatin E.[56,58] It has been designed to bind to the AXL receptor under high glycolytic metabolic conditions of the microenvironment of the tumor.[57] Upon its selective binding to the AXL receptor, undisclosed mechanisms of action performed by the cytotoxic agent result in the death of tumor cells.[56] The first-in-human phase 1 clinical trial administered mecbotamab by IV infusion with dose ranges, such as from 0.3–3 mg/kg Q3W, 1.2–1.8 mg/kg Q2W, and 1.8 mg/kg 2Q3W.[58] A total of 67 patients with advanced solid tumors were treated with mecbotamab in this trial. To date, additional results from the dose escalation portion of this trial have not yet been presented publicly, including adverse events, DLTs, MTDs, pharmacokinetics, and any correlative studies.[58]

A case report was published from this trial and reported the response observed in a 28-year-old woman with adenoid cystic carcinoma-II.[57] At the time of trial enrollment, the patient was highly symptomatic with dyspnea, requiring 2–4 L of oxygen continuously by nasal cannula due to extensive parenchymal lung and pleural metastases, with the largest measuring 3.9 cm. The patient’s treatment with mecbotamab was at the 1.8-mg/kg dose level, given via IV Q2W. Restaging scans at approximately 4 months after the beginning of her treatment showed a 25% reduction in target lesions and a disappearance of some lung nodules. In addition, the patient experienced symptomatic improvement and needed less supplemental oxygen. Initial side effects observed included fatigue, nausea, vomiting, anemia, elevated liver enzymes, and proteinuria. Ten months after her treatment began, she experienced grade 2 neuropathy, which required a dose reduction to 1.5 mg/kg.[57]

A phase 2 clinical trial evaluated mecbotamab in patients with AXL-expressing (tumor membrane percent score ≥ 50%) advanced refractory sarcoma.[59] Patients received either mecbotamab monotherapy 1.8 mg/kg Q2W or mecbotamab 1.8 mg/kg Q2W, combined with nivolumab. Of patients, 87 were treated in the monotherapy arm, and 26 patients were in the combination arm. More than 95% of patients in the monotherapy arm had received one or more prior lines of systemic therapies for metastatic disease, whereas all patients in the combination arm had prior lines of systemic therapies. The monotherapy arm enrolled 21 patients with soft tissue sarcoma, 19 with leiomyosarcoma, 12 with osteosarcoma, eight with Ewing sarcoma, 12 with other bone sarcomas, eight with liposarcoma, and seven with synovial sarcoma. The combination therapy arm included 12 patients with soft tissue sarcoma, eight with leiomyosarcoma, four with synovial sarcoma, one with liposarcoma, and one with osteosarcoma. TEAEs in the monotherapy arm included fatigue (43%), nausea (41%), decreased appetite (24%), diarrhea (23%), constipation (22%), anemia (21%), headache (21%), abdominal pain (20%), vomiting (19%), increased AST (18%), peripheral neuropathy (17%), and decreased neutrophil count (16%). In the combination therapy arm, TEAEs included fatigue (39%), decreased appetite (35%), nausea (31%), anemia (31%), constipation (27%), diarrhea (23%), headache (23%), vomiting (19%), increased AST (19%), peripheral sensory neuropathy (19%), abdominal pain (12%), and decreased neutrophil count (12%). On the monotherapy arm, two patients with osteosarcoma and one patient with undifferentiated pleomorphic sarcoma achieved PR.[59]

A phase 2, open-label trial evaluated the efficacy and safety of mecbotamab alone and in combination with nivolumab in patients with nonsquamous NSCLC.[60] Patients treated with monotherapy received IV mecbotamab at dosages of 1.8 mg/kg Q2W, 2Q3W, and 3Q4W. Those treated with both mecbotamab and nivolumab received 1.8 mg/kg Q2W. In the monotherapy arm, 23 patients were treated with mecbotamab. All patients had at least one prior line of systemic therapy. In the combination therapy arm, 17 patients were treated, and all patients had received at least one prior line of systemic therapy. The most frequent TEAEs observed in more than 20% of patients in both arms included fatigue, diarrhea, constipation, and decreased appetite. Patients with prior PD-1/PD-L1 treatment failure were assessed for efficacy at 12 weeks. Among those on the monotherapy arm who had been evaluated, the response rate was 27.8%, and the disease control rate was 55.6%. In the combination therapy arm, one patient had an ongoing CR, two patients experienced PR, and eight patients experienced SD.[60]

TAMNORZATINIB

Tamnorzatinib (ONO-7475; Ono Pharmaceutical Co., Ltd, Tokyo, Japan) is a novel, small-molecule inhibitor targeting AXL and MER tyrosine kinases. The inhibitor is designed to disrupt tumor cell proliferation and survival pathways. In a phase 1 trial, patients with advanced or metastatic solid tumors received tamnorzatinib (3, 6, and 10 mg, orally) either alone (n = 12) or in combination with nivolumab (240 mg, IV Q2W; n = 12).[61] One patient in the 10-mg combination cohort experienced DLTs, including grade 4 nephritis, grade 3 colitis, and grade 3 hepatic function abnormalities. Tamnorzatinib was tolerated up to 10 mg as a monotherapy and in combination with nivolumab. Pharmacodynamic analysis showed that serum GAS6 levels were suppressed effectively. Pharmacodynamic results also indicated activation of T-cell function and an increased ratio of inflammatory to immunosuppressive macrophages. The objective response rate was 8.3%, and the disease control rate was 33.3% in the combination therapy group.[61]

A phase 1/2 study of tamnorzatinib was performed in patients with AML and myelodysplastic syndromes, as either monotherapy or in combination with venetoclax.[62] Although results were not presented in an abstract or publication through a peer-reviewed process, preliminary results were posted on clinicaltrials.gov. In part A, tamnorzatinib was administered orally at doses of 3, 6, and 10 mg once daily. In part D, tamnorzatinib was given in combination with venetoclax, which was given at doses in the range of 70–400 mg. The study design for parts B and C was not disclosed by the trial sponsor. A total of 42 patients were treated. No DLTs were reported, and MTD was not reached. Pharmacokinetic analysis showed a mean C_max of 622 ng/mL at 6 mg on the venetoclax combination. Analysis of pharmacodynamics showed the inhibition of AXL and MER in plasma samples. Of the 13 patients assessed in part A, none achieved SD, PR, or CR. Of the 20 patients assessed in part D, one patient achieved CRi (5%) and two achieved PR (10%).[63]

TILVESTAMAB

Tilvestamab, (BGB 149; BergenBio ASA, Bergen, Norway) is an anti-AXL function-blocking immunoglobulin G1 monoclonal antibody.[64] In preclinical studies, tilvestamab has been shown to bind to AXL tyrosine kinase and inhibit GAS6-induced activation of AXL, thus halting its downstream phosphorylation. In PROC, AXL expression is linked to poor prognosis due to its association with resistance to platinum chemotherapy and a mesenchymal gene expression molecular subtype (GEMS). The first in human phase 1 trial enrolled 16 patients with PROC who had previously received more than two lines of therapy.[65] The mean age of patients was 60.6 (±9.7) years. The GEMS of these patients included mesenchymal (n = 10), epithelial-B (n = 4), and stemlike-A (n = 1). Tilvestamab was administered via IV at concentrations of 1, 3, or 5 mg/kg twice weekly. The mean duration of treatment was 10.5 (±6.3) weeks. No TRAEs nor DLTs were reported. Five patients experienced SD. One patient with a mesenchymal subtype treated at 5 mg/kg achieved a 44% reduction in CA-125. Tilvestamab demonstrated dose-proportional pharmacokinetics. Pharmacodynamics were evaluated in tissue collected from two sequential biopsies, one before treatment and one after 28 days of treatment. AXL expression was significantly reduced because of the monotherapy. Phenotypic change from mesenchymal GEMS to Epithelial-B GEMS was observed in two patients. Tilvestamab was well tolerated across the doses investigated and showed evidence of on-target pharmacodynamic changes.[65]

DISCUSSION

AXL-selective inhibitors that have entered clinical trials have enrolled patients with many tumor types, including sarcomas, NSCLC, PROC, ccRCC, PDAC, urothelial cancer, as well as AML. AXL-directed agents that have been investigated have included monoclonal antibodies, ADCs, and TKIs. The most promising antitumor activity observed in clinical trials so far has been observed in NSCLC, PROC, ccRCC, and AML. In the phase 1 trial of bemcentinib with docetaxel, 35% of patients with radiographically evaluable disease achieved PR.[38] In the phase 2 trial combining bemcentinib and pembrolizumab in NSCLC, the ORR was 29%, including patients with the EGFR mutation. In the phase 1b trial of batiraxcept in combination with paclitaxel for patients with PROC, the ORR was 34.8%, including two patients with CR.[31] In the phase 2 trial of batiraxcept in combination with cabozantinib in ccRCC, the ORR was 46%, with a 6-month progression-free survival of 79%.[30] In the phase 1b trial of combination batiraxcept, gemcitabine, and nab-paclitaxel in patients with PDAC, the ORR was 29%, with a mOS of 12.3 months.[29] In the phase 1b/2 trial of dubermatinib for TP53-mutated AML in combination with decitabine, four patients achieved CR, four CRh, two CRi, and six minimal residual disease (of patients who achieved CR).[48] In other clinical trials of dubermatinib, objective responses were observed in patients with NSCLC, melanoma, and cholangiocarcinoma.

Among the selective AXL inhibitors assessed, DLTs as monotherapy were only reported for two of the agents. The first-in-human phase I dose-escalation trial of EnaV monotherapy had DLTs of constipation, vomiting, γ-glutamyl transferase increase, febrile neutropenia, and diarrhea. The first-in-human phase 1 dose-escalation study of dubermatinib as monotherapy had one DLT of grade 4 thrombocytopenia. These limited results preclude establishing a toxicity pattern for this drug class, and the pending safety results of the other AXL inhibitors are eagerly anticipated. However, these agents have been tolerated well enough as monotherapy to be considered for many combinations that have been investigated, including with cytotoxic agents, targeted agents, and immunotherapy. Safety data from these combination studies generally reflect the toxicity profile of the combination agent, especially cytopenias in the combinations with chemotherapy.

AXL-specific inhibitors reviewed were orally or IV administered. Although most AXL inhibiting agents reviewed demonstrated dose-proportional pharmacokinetics, increased exposure to DS-1205c and batiraxcept showed lower-than-expected dose proportionality. ^[28,44] The half-lives of oral drugs were generally shorter than those of IV drugs. This was seen in dubermatinibm, which was given orally and had the shortest reviewed half-life of 12–20 hours.[46] The AXL inhibitor with the longest half-life of 4 days was micbotomab vedotin, which was administered via IV.[66] The dosing schedules also varied for the two aforementioned drug administration modes. AXL inhibitors administered orally had a more frequent dosing schedule as seen in bemcentinib, dubermatinib, and tamnorzatinib, which were given orally once daily compared to tilvestamab, enapotomab vedotin, and batiraxcept, which were administered as IV infusions in dosing schedules ranging from one to three times every 1–4 weeks.

AXL inhibitors are being tested in combination strategies with EGFR inhibitors, ATR inhibitors, BRAF inhibitors, and PD-1/PD-L1 immune checkpoint inhibitors. A recent xenograft mouse model study found that brigatinib, a second-generation ALK inhibitor, potently inhibits AXL expression. After designating brigatinib as a newly discovered AXL inhibitor, the study tested combination strategies of brigatinib with osimertinib (an EGFR inhibitor) on cells with acquired osimertinib resistance and high AXL expression. After 3 weeks of treatment, osimertinib monotherapy had no antitumor effect, brigatinib monotherapy caused slight tumor growth inhibition, and osimertinib and brigatinib combination therapy caused substantial tumor shrinkage, suggesting potential antitumor synergy between AXL inhibitors and EGFR inhibitors.[67] A study of pleural mesothelioma cells found that an AXL/ATR inhibition combination strategy greatly increased malignant cell apoptosis and decreased cell viability when compared with monotherapy strategies.[68] Another study, using ATR inhibitor-resistant NSCLC cells and ATR inhibitor-resistant large cell neuroendocrine carcinoma cells, reported that AXL and ATR inhibitor combination therapy led to a decrease in cell viability greater than the predicted additive effect.[69] A study using ID8 tumors in C57BL/6 mice showed that the efficacy of a PD-1/PD-L1 immune checkpoint blocker was greatly enhanced when given in combination with AXL inhibitors (SGI-7079 and R428). The median survival was 27 days for untreated mice, 28.5 days for mice treated with PD-1 inhibitor monotherapy, 54.5 days for mice treated with SGI-7079 monotherapy, and 78.5 days for mice treated with SGI-7079/PD-1 inhibitor combination therapy. Mice treated with R428/PD-1 inhibitor combination therapy had an even longer (not reached) median survival.[70]

Efforts to identify a potential selective biomarker for AXL inhibitors are currently ongoing. In a preclinical study, EMT 76-gene signature was developed to propose AXL as a biomarker of EGFR-inhibitor resistance in 54 NSCLC cell lines. Cell lines classified by the EMT as mesenchymal were observed to express AXL at high concentrations and demonstrate sensitivity to AXL inhibitor SGI-7079.[71] In the phase 1b/2 trial of the combination of batiraxcept and cabozantinib in patients with ccRCC, the ORR among all patients was 46%; however, among patients with a soluble AXL (sAXL)/GAS6 ratio of more than 2.3, the ORR was 67%, suggesting that higher sAXL expression may be a promising biomarker.[31] In the phase 2 study of bemcentinib with pembrolizumab in patients with advanced lung adenocarcinomas (n = 48), of 28 biomarker-evaluable patients, 50% expressed AXL on tumor tissue. The progression-free survival of AXL-positive patients was 5.9 months, in comparison to 4 months for all patients, suggesting that tumor expression of AXL could be a promising selective biomarker.[72] In a phase 3, placebo controlled, double-blind trial of batiraxcept + paclitaxel and placebo + paclitaxel in patients (n = 366) with PROC, ORR was 25.1% in the batiraxcept + paclitaxel group and 26.2% in the control group. Of the 304 evaluated tumors, 20% overexpressed AXL. Patients with tumors that overexpressed AXL achieved a higher mPFS (5.78 months) and mOS (17.8 months) in the batiraxcept paclitaxel study arm than in the control arm (mPFS 3.71 months, mOS 8.11 months).[32] The results of this trial suggest patients with AXL overexpression were more sensitive to AXL inhibitor treatment and experienced more efficacious results than the total patients enrolled. In a preclinical study, AXL3 was identified as a potential biomarker and therapeutic target for the treatment of mantle cell lymphoma. AXL3 is an AXL isoform that lacks a ligand-binding domain and is not activated via the GAS6 pathway. CRISPR inhibition of AXL3 was discovered to induce apoptosis of mantle cell lymphoma cells.[81] Further investigation is needed to validate these early results and establish AXL tissue expression and/or sAXL as predictive biomarkers for AXL-direct treatment strategies.

CONCLUSION

In summary, AXL inhibitors are a promising class of drugs that have demonstrated antitumor activity in patients with a range of solid tumors as well as hematologic cancers at the early clinical stages. Further clinical trials are warranted to investigate the efficacy and tolerability of AXL selective inhibitors in different tumor types, as a monotherapy or in combination.