Phase II study of axitinib in patients with NF2-related schwannomatosis and progressive vestibular schwannomas

Abstract

Background

Axitinib is an oral multi-receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and c-KIT. These represent a clinically and/or preclinically validated molecular targets in vestibular schwannoma (VS).

Methods

Eligible patients were age > 5 years with a clinical diagnosis of NF2-related schwannomatosis (NF2-SWN) and at least one volumetrically measurable, progressive VS. Axitinib was given continuously in 28-day cycles for up to of 12 cycles. Primary endpoint was objective volumetric response rate to axitinib, hearing response was a secondary endpoint, along with validated quality of life assessments (NFTI-QOL).

Results

Twelve patients were enrolled and 8 completed 12 cycles, including 2 pediatric patients. Ten patients were evaluated for the primary endpoint, defined as ≥ 20% decrease in VS volume, with 2 volumetric responses observed; both were reached after 3 cycles and sustained during treatment. The best volumetric response was −53.9% after 9 cycles. Three hearing responses were observed, one of which was sustained during treatment. All patients experienced drug-related toxicities, the most common were diarrhea, hematuria, and skin toxicity, not exceeding grade 2, as well as hypertension, not exceeding grade 3. NFTI-QOL scores remained stable or improved during treatment.

Conclusions

Axitinib therapy targeting VEGFR, PDGFR and c-KIT is feasible in this population and associated with volumetric and hearing responses in a subset of patients. However, convenience of oral administration should be balanced with respect to efficacy and safety of axitinib in comparison with other molecular-targeted therapies, including intravenous bevacizumab.

Key Points.

• Axitinib has objective anti-tumor activity in NF2-SWN VS patients and is reasonably well tolerated in this population

• Further studies are needed to optimize molecular-targeted therapies for NF2-SWN patients

Importance of the Study.

Progressive VS in individuals with NF2-SWN are associated with major functional impairments and morbidity. We hypothesized that muti-kinase targeted oral therapy with axitinib might be more convenient and effective compared to VEGF-A targeted therapy with bevacizumab. We show that axitinib therapy is feasible and associated with objective anti-tumor activity including hearing improvement in a subset of NF2-SWN patients with VS. Further studies are needed to compare toxicity and response rates with other treatment options such as bevacizumab and to optimize molecular-targeted therapies for NF2-SWN patients with the goal of increasing efficacy and tolerability.

NF2-related schwannomatosis (NF2-SWN) is an autosomal dominant genetic disorder with an incidence of approximately 1 in 50,000.¹ It is caused by germline or mosaic pathogenic variants in the NF2 tumor suppressor gene located on chromosome 22q. NF2-SWN patients develop central and peripheral nervous system tumors, most commonly vestibular schwannoma (VS) and other cranial nerve schwannomas, meningiomas, and ependymomas.² VS are slow-growing tumors associated with progressive neurological deficits and significant morbidity such as sensorineural hearing loss, tinnitus, ataxia, vertigo, facial palsy, and brainstem compression. The treatment goals for NF2-SWN patients with VS are to reduce or stabilize tumor size, and if possible, restore or at least preserve function.³

Axitinib is an oral multi-receptor tyrosine kinase (RTK) inhibitor targeting vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and c-KIT. Axitinib inhibits VEGFR1/2/3, PDGFRα/β and c-KIT phosphorylation at sub– to low nanomolar concentrations.⁴ Axitinib is currently FDA-approved for the treatment of adult patients with renal cell carcinoma.⁵ In children with refractory solid tumors, the maximum tolerated and recommended dose of axitinib was determined to be 2.4 mg/m²/dose, providing pharmacokinetic exposures similar to those of adults.⁶

All of the molecular targets of axitinib represent clinically and/or preclinically validated molecular targets for VS: (1) VEGFR: Angiogenesis occurs in VS, and VEGFRs are expressed in these tumors.^7–9 Anti-VEGF(R)-directed therapy with bevacizumab and vandetanib normalized the vasculature of NF2^-/- schwannoma xenografts in nude mice and decreased tumor growth.¹⁰ In prospective clinical trials, VEGF-targeted therapy with bevacizumab led to sustained tumor shrinkage and hearing improvement in NF2-SWN patients with VS.^11,12(2) PDGFR: Schwann cells express PDGFRα and PDGFRβ.¹³ Signaling through these receptors activates the RAS-RAF-MEK-ERK and PI3K-AKT signaling pathways, and is important for Schwann cell proliferation in vivo and in vitro.^14–16 Overexpression of PDGFRβ has been observed in VS,^17–19 and PDGFR inhibitors including AG1296, imatinib, and nilotinib are effective in preventing PDGFR-driven proliferation when assessed in VS in vitro models.^17,20(3) c-KIT: VS express activated c-KIT and are growth-inhibited by imatinib¹⁹ and nilotinib.²⁰

In summary, we reasoned that the molecular target profile of axitinib supported its clinical assessment as a promising drug candidate for clinical study in NF2-SWN patients with progressive VS. We conducted a single-center, prospective, 2-stage, open-label phase II study to estimate the response rate to axitinib in this population.

Patients and Methods

Patient Eligibility and Enrollment

Patients (age ≥ 5 years) meeting contemporary NF2 clinical diagnostic criteria^21,22 were eligible for enrollment. Additional eligibility criteria included Karnofsky (> 16 years) or Lansky (≤ 16 years) performance status of ≥ 60, at least one NF2-SWN related, volumetrically measurable (i.e. ≥ 1 cc) VS with either volumetric progression or hearing loss over the preceding 18 months designated as the primary target tumor, and adequate organ system function (i.e. bone marrow, renal, hepatic). Histological confirmation was not required, as these tumors rarely require biopsies. For eligibility, progressive tumor growth (defined as either > 2 mm increase in maximum linear diameter on conventional MRI, or a > 20% volume increase by volumetrics)⁸ over the past ≤ 18 months. A contralateral VS, if present and volumetrically measurable (≥ 1 cc), was designated as an additional target tumor. Key exclusion criteria included major surgery or significant traumatic injury, prior anti-cancer therapies, or any investigational drug and radiation within 4 weeks of the start of the study drug. Other exclusion criteria were prior therapy with agents targeting VEGF or VEGFR, unstable or rapidly progressive disease, known preexisting uncontrolled cardiac, lung, or liver disease, significant impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of axitinib, active bleeding diathesis, concurrent therapy with cytochrome P450 3A4 inducers or inhibitors, and pregnancy or breastfeeding in female patients.

The study was conducted under a protocol approved by the institutional review boards of NYU Langone Health and Memorial Sloan Kettering Cancer Center, and registered at ClinicalTrials.gov (NCT02129647). Informed consent was obtained from the patients and guardians in accordance with institutional policies. All consecutive patients who met the study entry criteria and who consented to participate were enrolled.

Study Design

This was a prospective, single-institution, 2-stage, phase II open-label study. The primary objective was to estimate the volumetric response rate to axitinib in participants with NF2-SWN-related progressive VS. Secondary objectives included toxicity assessments of axitinib and analysis of the association of objective measures of imaging with clinical measures of response (i.e. audiogram) and impact on quality of life (QOL) using validated questionnaires. A 2-stage Simon design²³ was used to test the null hypothesis of a volumetric response rate ≤ 5%, against the alternative hypothesis of a volumetric response rate ≥ 25%. Nine patients were to be enrolled in Stage 1. If at least one patient of these 9 had a volumetric response in Stage 1, at any given evaluation point, an additional 8 patients were to be enrolled in Stage 2. The overall alpha level for this design was 0.05 with a power of 80%. Axitinib was to be considered effective and of interest for further study if, after successful completion of both stages, there were at least 3 responses in the combined stages.

Treatment Plan

Axitinib was provided by Pfizer, administered in continuous 4-week courses, and was available in 1 mg and 5 mg tablets. Given the known high interpatient variability of axitinib drug exposures, a “flexible dosing” method is recommended.²⁴ Consistent with axitinib prescribing information, patients (≥ 18 years of age) received 5 mg twice daily (dose level 0), approximately 12 hours apart as a starting dose. Those with no adverse events related to axitinib above CTCAE Grade 2 for 2 consecutive weeks, were normotensive, and did not receive anti-hypertension medication had their dose increased sequentially to 7 mg twice daily (dose level + 1), and 10 mg twice daily (dose level + 2) after another 2 consecutive weeks. Those who had adverse events had their dosage reduced to 3 mg twice daily (dose level −1) and if needed to a minimum of 2 mg twice daily (dose level −2).

Pediatric patients (< 18 years of age) received 2.4 mg/m² twice daily (dose level 0). Those with no adverse events related to axitinib above CTCAE Grade 2 for 2 consecutive weeks, were normotensive, and did not receive anti-hypertension medication had their dose increased to 3.2 mg/m² twice daily (dose level + 1) and those who experienced adverse events had a dose reduction to 1.8 mg/m² twice daily (dose level -1).

Basic clinical evaluations including a complete blood count with differential, comprehensive metabolic panel, and urinalysis, were performed at baseline, on day 1, weeks 2 and 3 of the first course and every 5 weeks thereafter. Serum thyroid studies and pregnancy tests (for females of child-bearing potential) were performed every 5 weeks starting with the second cycle. In addition, screening electrocardiogram and plasma international normalized ratio were obtained at baseline. Patients were allowed to remain on treatment until disease progression or unacceptable toxicity occurred. Adverse events were graded using 4.0 of the National Cancer Institute Common Toxicity Criteria (CTCAE). For patients who were unable to tolerate the protocol-specified dosing schedule, drug dosing was interrupted or modified according to protocol-prespecified rules. For treatment interruptions due to adverse events, therapy had to be held until toxicity was sufficiently improved, to grade ≤ 1 or baseline.

Response Evaluation

MRIs of the brain were performed at baseline and after every 12 weeks and tumor volumetrics were obtained on postcontrast, T1-weighted magnetization-prepared rapid acquisition with gradient echo sequences with 1-mm slice thickness and no gap, using semi-automated segmentation software (Vitrea platform) as previously described.²⁵ Volumetric response and progression were defined as ≥ 20% decrease or increase in tumor volume, respectively. In patients with remaining hearing, serial audiological evaluations were performed at baseline, and subsequently at the time of each MRI, including the determination of word recognition score (WRS) using the 50-item recorded CID (Central Institute for the Deaf)-W22 monosyllable word list. Hearing improvement and progressive hearing loss were defined as an increase or decline in WRS above or below the 95% critical difference threshold from the baseline score, respectively.²⁶ Volumetric and hearing response criteria were consistent with consensus recommendations from the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration.^27,28 Study treatment was discontinued for volumetric progression in a primary target tumor, i.e. ≥ 20% enlargement from baseline.

QOL Assessments

NF2-SWN specific QOL assessments were performed in patients ≥ 18 years of age using a standardized questionnaire (NFTI-QOL) at baseline and cycle 6.²⁹ This validated questionnaire assesses the domains of hearing, dizziness and balance, facial palsy, sight, mobility and walking, role and outlook on life, pain, and anxiety and depression. Scores range from 0 (not present) to 3 (stops usual activities) for each domain, and higher total scores represent worse QOL. The added scores result in a final score range of 0–24, with higher scores representing worse disease-specific QOL.

Statistical Analysis

Disease and patient characteristics at baseline were summarized using descriptive analysis. Progression-free survival (PFS) was measured from the first date of the study drug to the date of volumetric or hearing progression, whichever event occurred first. PFS was summarized using Kaplan–Meier methods for overall PFS. Point estimates for PFS with 95% confidence intervals were calculated. Overall response rates were estimated with exact Clopper–Pearson 95% confidence intervals.

Results

Study Participants

A total of 12 eligible participants were enrolled between January 2015 and January 2018. Two patients were non-evaluable due to discontinuing study treatment prior to the first scheduled response evaluation: one withdrew from the study for personal reasons and one for noncompliance. The total number of evaluable target tumors in the 10 evaluable patients was 12. A summary of general patient characteristics at enrollment is provided in Table 1, and hearing distribution in enrolled ears at baseline is shown in Supplementary Table S1. All 10 evaluable participants had a (dominant) VS selected as the primary target tumor, with 2 participants having volumetrically measurable bilateral VS, totaling 12 target tumors. Stage 2 of the study was opened for enrollment after the first volumetric response was observed among 9 evaluable participants treated on Stage 1. Due to slowing accrual on Stage 2, planned total enrollment of 17 evaluable subjects was not reached. There were 7 (58.3%) males and 5 (41.7%) females, with a median age of 39 years at enrollment (range, 14–55), including 2 pediatric patients < 18 years of age. Each participant or their legal representative(s) provided written informed consent for treatment, as applicable.

Table 1.

Summary of general patient characteristics at enrollment

Participant	Age (years)	Sex	Target tumor size left/right (cc)	Baseline WRS of target left/right tumors (%)	Baseline PTA of target left/right tumors (dB)
1	20	M	NA/6.54	NA/68	NA/63
2	22	F	1.62/NA	30/NA	99/NA
3	51	F	11.95/2.31	NA/NA	NA/NA
4*	41	M	6.07/NA	88/66	16/50
5	52	M	-/3.78	NA/50	NA/75
6	19	M	1.68/7.53	100/100	26/19
7	50	F	-/5.60	100/80	11/41
8	52	F	NA/1.65	100/88	4/23
9	37	F	2.17/NA	100/NA	6/NA
10	15	M	4.58/NA	100/NA	3/NA
11*	55	M	5.58/NA	76/NA	75/NA
12	14	M	-/1.20	100/100	9/11

Abbreviations: F = female; M = male; WRS = word recognition score; PTA = pure tone average; NA = not applicable (for WRS and PTA, NA indicates complete deafness).

^*Denotes non-evaluable patients.

Treatment Administered

The median number of courses received by the 10 evaluable participants was 12 (range, 3–12). Two patients came off trial due to volumetric progression after 9 and 3 courses, respectively. Eight participants completed 12 courses, at which time 2 met criteria for progression.

Toxicity and Dose Reductions

All 12 participants were available for toxicity monitoring. One participant (10%) experienced grade 3 toxicity: hypertension. Observed toxicity was otherwise minor (CTCAE 4.0 grades 1 and 2) and most commonly included diarrhea (90%), hypertension (80%), hematuria (70%), fatigue (50%) and skin toxicities (50%), all of which were expected. No grade 4 toxicity was observed. The maximum dose level (+ 2) of 10 mg twice daily was reached in 5/10 evaluable participants (50%), and 4/10 participants (40%) required dose reductions for drug-related toxicities according to protocol. A summary of dose escalations and reductions is provided in Table 2.

Table 2.

Summary of dose escalations and reductions

Participant	Last dose level	Maximum dose level	If < + 2, reason:	Dose reduction? Y/N	Reason for dose reduction
1	7 mg BID	+2	NA	Y	Diarrhea
2	10 mg BID	+2	NA	N	NA
3	5 mg BID	0	Hypertension	N	NA
4*	5 mg BID	+2	NA	N	Patient-directed dose
5	7 mg BID	+2	NA	Y	Hypertension
6	5 mg BID	0	Hypertension	N	NA
7	7 mg BID	+2	NA	Y	Skin toxicity
8	5 mg BID	0	Hypertension	N	NA
9	7 mg BID	+2	NA	Y	Diarrhea
10	6 mg AM 5 mg PM	+1#	NA	N	NA
11*	3 mg BID	0	NA	Y	Hypertension
12	6 mg BID	+1#	NA	N	NA

^*Denotes non-evaluable patients.

^#+1 is the maximum dose level for pediatric patients.

Dose levels:  + 2 = 10 mg BID, + 1 = 7 mg BID, 0 = 5 mg BID, -1 = 3 mg BID, -2 = 2 mg BID.

Volumetric and Hearing Responses

Baseline patient characteristics at enrollment are summarized in Table 1. A summary of all tumor volumes before and during protocol therapy is provided in Table 3. Maximum change in tumor volume during protocol therapy for all target VS compared to baseline is shown in Figure 1. Two participants experienced an objective volumetric response in a primary target tumor, with −53.9% and −35.2% tumor shrinkage after 9 and 6 courses, respectively. Five participants experienced stable disease and 3 experienced volumetric progression in a primary target tumor during treatment. Among all 12 target tumors, volumetric response was observed in 2, stable disease in 6, and progression in 5.

Table 3.

Summary of tumor volume for all patients

Participant	Volume (% change from baseline)
	Baseline	Course 3	Course 6	Course 9	Course 12
1R	6.54	6.76 (3.4)	7.06 (8.0)	7.65 (17)	8.54 (30.6)
2L	1.62	1.40 (-13.6)	1.59 (-1.9)	1.72 (6.2)	1.53 (-5.6)
3R	2.31	2.08 (-10)	1.87 (-19)	1.98 (-14.3)	2.28 (-1.3)
3L	11.95	10.84 (-9.3)	10.57 (-11.5)	9.93 (-16.9)	12.05 (0.8)
4L*	6.07
5R	3.78	3.41 (-9.8)	3.73 (-1.3)	3.58 (-5.3)	4.01 (6.1)
6R	7.53	7.77 (3.2)	8.79 (16.7)	9.38 (24.6)
6L	1.68	1.60 (-4.8)	1.66 (-1.2)	1.94 (15.5)
7R	5.60	4.07 (-27.3)	4.03 (-28)	2.58 (-53.9)	2.60 (-53.6)
7L	0.23	0.26 (13)	0.26 (13)	0.24 (4.3)	0.25 (8.7)
8R	1.65	1.09 (-33.9)	1.07 (-35.2)	1.11 (-32.7)	1.11 (-32.7)
9L	2.17	2.79 (28.6)
10L	4.58	4.85 (5.9)	5.22 (14)	5.17 (12.9)	5.38 (17.5)
11L*	5.58
12R	1.20	1.33 (10.8)	1.34 (11.7)	1.39 (15.8)	1.60 (33.3)

Volume expressed in cc (% change).

^*Denotes non-evaluable patients.

Abbreviations: R = participant right side tumor; L participant left side tumor; NA = not applicable.

Volumetric responses are denoted in bold, volumetric progression in bold italic.

Figure 1.

Waterfall plot of the percentage of change in tumor volume, from baseline, for each evaluable target tumor (n = 12). Each column represents a volumetrically measurable individual VS. For each tumor, the best response while on study is shown. For tumors that did not show any volume reduction, the largest percentage of volumetric growth during therapy is indicated.

A summary of WRSs is provided in Table 4. Excluding patients without remaining hearing or hearing above the threshold to be able to achieve an objective hearing response at baseline in a target ear, 3/5 patients had sufficient improvement in WRS to meet the definition of a hearing response. The responses were observed after a median of 3 courses (range, 3–12), and sustained throughout treatment in one patient. Of note, a combined volumetric and hearing response of a primary target VS was observed in 2 patients. None of the participants experienced a hearing decline during protocol therapy. A summary of pure tone averages for all patients is shown in Supplementary Table S2.

Table 4.

Summary of WRSs for all patients

Participant	WRS left/right (%)
	Baseline	Course 3	Course 6	Course 9	Course 12
1	NA/68	NA/74	NA/58	NA/66	NA/86
2	30/NA	20/NA	18/NA	32/NA	20/NA
3	NA/NA	NA/NA	NA/NA	NA/NA	NA/NA
4*	88/66	–/–	–/–	–/–	–/–
5	NA/50	NA/48	NA/48	NA/64	NA/64
6	100/100	100/96	100/100	100/100	–/–
7	100/80	96/96	100/92	100/78	100/80
8	100/88	100/100	100/100	100/100	100/100
9	100/NA	100/NA	–/–	–/–	–/–
10	100/NA	100/NA	100/NA	–/–	–/–
11*	76/NA	–/–	–/–	–/–	–/–
12	100/100	100/100	–/100	100/100	–/–

^*Denotes non-evaluable patients.

Abbreviations: WRS = word recognition score; PTA = pure tone average; NA = not applicable.

Hearing responses denoted in bold.

PFS and Median Time to Progression

Four patients experienced volumetric progression at a median time of 10 months (95% confidence interval), as shown in Figure 2.

Figure 2.

Kaplan–Meier estimates of cumulative PFS probability. This figure illustrates the overall (black line) PFS probability as measured from first dose of study drug to date of progression for all evaluable VS. Dashed lines indicate 95% confidence intervals.

Quality of Life

Six participants ≥ 18 years of age completed QOL assessments at both baseline and cycle 6, 5 of which were eligible for improvement in QOL with a baseline score of ≥ 2. there was no change in 2 and a one-point improvement in the remaining 3, as shown in Supplementary Table S3.

Discussion

Over the past decade, several medical treatment options for NF2-SWN related VS have emerged. Preclinical studies using in vitro and in vivo models have identified molecular targets including mammalian target of rapamycin (mTOR)^30–32 and tyrosine kinases, such as VEGFR,¹⁰ EGFR,^33,34 ErbB2,³⁴ PDGFR,^19,20 c-KIT,¹⁹ PI3K³⁵ and FAK,^36,37 leading to successfully completed prospective clinical trials^{11,12,25,38,39} and ongoing studies.⁴⁰ To date, the highest imaging response rates in VS have been observed with intravenous administration of the humanized anti-VEGF-A monoclonal antibody bevacizumab, along with sustained hearing improvement in a subset of patients.^11,12

Axitinib is an oral multi-RTK inhibitor targeting VEGFR1/2/3, PDGFRα/β, and c-KIT.⁴ We hypothesized that this target profile might result in superior anti-tumor efficacy compared to bevacizumab, without the need for intravenous administration.

While we fell short of the total planned accrual of 17 evaluable subjects due to competing studies and increasing off-label use of bevacizumab, we were able to draw several meaningful conclusions from 10 participants treated with axitinib who were evaluable for response.

Overall, treatment was feasible following the protocol-prescribed dose escalation and reduction plan, consistent with current prescribing information for axitinib. Observed toxicities were anticipated and generally minor, with one exception of grade 3 hypertension.

Considering all 12 target tumors, rates of volumetric response, stable disease and progression on treatment with axitinib were 2/12 (17%), 6/12 (50%) and 4/12 (33%), respectively. In a prior phase 2 trial with lapatinib, the corresponding rates were 5/22 (22%), 13/22 (59%) and 4/22 (18%), respectively, with the caveat that this particular study considered a ≥ 15% change in volume threshold for response and progression instead of ≥ 20%. In a prospective trial with bevacizumab, the reported rates of volumetric response, stable disease and progression were 15/41 (37%), 24/41 (59%) and 2/41 (5%), respectively, during 6 months of induction therapy.¹² During subsequent maintenance therapy with bevacizumab, 6/37 (16%) of VS progressed.⁴¹ Remarkably, the volumetric response rates to bevacizumab in pediatric patients ≤ 21 years of age were noted to be significantly lower compared to adults, with only a single volumetric response observed among 12 pediatric VS (8%).¹² Recently published results from a prospective trial with brigatinib, an inhibitor of ALK and multiple non-RTK, showed volumetric response and progression rates of 10/43 (23%) and 16/43 (37%).⁴²

Similarly, we observed no volumetric responses to axitinib among 5 tumors in patients < 21 years of age, consistent with the notion that VS in young patients with early-onset disease tend to be more aggressive and less responsive to anti-angiogenic therapy. In participants who did experience a volumetric response on axitinib, the observed tumor shrinkage of −53.9% and −35.2% compares favorably to results with bevacizumab and brigatinib, although a direct comparison between studies cannot be made.^12,42

Regarding functional outcome, we observed a hearing response in 3/5 evaluable participants at some point during treatment, however, only one was sustained. In comparison, 11/28 evaluable ears achieved a hearing response during bevacizumab induction therapy while 13/37 ears had improvement in hearing intelligibility, and 10/44 ears had improvement in hearing sensitivity on brigatinib.^12,42 It is important to mention that the percentage of patients without decrease in hearing sensitivity and hearing intelligibility while on brigatinib were 89% and 74%, respectively.⁴² Of note, none of the participants in our study experienced a hearing decline on axitinib.

In terms of toxicity in the NF2-SWN population, axitinib appeared to be associated with higher rates of diarrhea, hypertension, fatigue and skin toxicities when compared to other studies with bevacizumab and brigatinib.^11,12,41,42 Regarding NF2-SWN related QOL, we observed overall stable to slightly improved scores during axitinib therapy, however, the small number of 5 patients assessable for improvement precluded formal statistical analysis. In comparison, statistically significant improvement in QOL was reported in 32% of participants during bevacizumab induction therapy.¹²

Based on our observations, we conclude that while axitinib has objective anti-tumor activity against NF2-SWN related VS, convenience of oral administration should be balanced with respect to efficacy and safety of axitinib in comparison with other molecular-targeted therapies, such as intravenous bevacizumab. While we originally intended for axitinib to target VEFR, PDGFR and c-KIT in this study, it appears to primarily act as a VEGFR tyrosine kinase inhibitor at the clinically achievable exposure,^5,43 which might explain, at least in part, the clinical results we observed. Whether more “balanced” inhibitors of VEFR, PDGFR and c-KIT, such as pazopanib,⁴⁴ might be more effective, is an open question. Another multi-kinase inhibitor, crizotinib,³⁶ with activity against focal adhesion kinase (FAK) are under investigation in recently completed or ongoing clinical trials.⁴⁰ A novel class of inhibitors against the previously considered “undruggable” target relevant to NF2-deficient tumors, transcriptional enhanced associate domain transcription factor,⁴⁵ has shown promise in preclinical studies for NF2-SWN related schwannoma⁴⁶ and early-phase human trials are in progress.^47,48

Further studies will be necessary to improve molecular-targeted therapies for those affected by NF-SWN with the goal of increasing anti-tumor efficacy, while minimizing toxicity and improving functional outcomes, as well as QOL.

Funding

This study was supported by Pfizer, Inc. and funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748 to Memorial Sloan Kettering Cancer Center.

Conflict of interest statement. MAK received research funding for this study from Pfizer, Inc. All other authors declare that they have no relevant conflicts of interest.

Author contributions

Experimental conception and design: MAK, JDG, JCA. Collection and assembly of data: MAK, AY, CM, SA, TN, SSP, KY, JCA. Data analysis and interpretation: MAK, MRG, SSP, YF, JDG. Manuscript writing: MAK, MRG. Final manuscript approval: all authors. Accountable for all aspects of the work: all authors.

Data availability

Data sharing is not applicable to this article.