Activating mutations of the anaplastic lymphoma kinase (ALK) gene were identified in the pediatric tumor neuroblastoma, in 2008. Rapid translation of this finding into targeted neuroblastoma therapy was facilitated by the availability of ALK inhibitors developed for adult malignancies and an efficient preclinical and clinical research program.

See related article by Foster et al., p. 3543

In this issue of Clinical Cancer Research, Foster and colleagues report outcomes in 20 patients with relapsed or refractory neuroblastomas harboring activating alterations of anaplastic lymphoma kinase (ALK) treated in the phase I/II open-label trial, ADVL0912, with the ALK inhibitor (ALKi), crizotinib, at the recommended phase II dose (1). The favorable toxicity profile previously reported for phase I (2), is confirmed in phase II by Foster and colleagues.

Neuroblastoma is the most common extracranial childhood tumor, accounting for 15% of all childhood cancer deaths. Despite a significant increase in treatment intensities, including autologous stem cell transplantation and immunotherapy, >50% of patients with high-risk neuroblastoma relapse, with poor long-term overall survival of <20%. Development of new approaches to treat high-risk and relapsed neuroblastoma is, therefore, a most urgent medical need. Activating point mutations in ALK were discovered in up to 15% of neuroblastomas in 2008, the most frequent being the Arg1275 and Phe1174 mutations (3). Approximately 2% of all neuroblastomas harbor ALK amplifications, also increasing ALK activity. Therefore, ALK alterations in neuroblastoma differ fundamentally from the ALK fusion genes identified in other malignancies such as lung carcinomas and lymphomas.

While low patient numbers have always made clinical trials in pediatric oncology challenging, it is even more challenging to recruit patients with a specific tumor subtype and specific molecular alterations. Foster and colleagues (1) chose a Simon two-stage 10+10 design and “borrowed” 6 patients from the phase I cohort to appropriately deal with the limited number of patients with ALK-positive neuroblastoma. This is the first phase II data reported for patients with ALK-positive neuroblastoma who were treated with an ALKi to date, and has long been awaited by the neuroblastoma community. Foster and colleagues report a response rate of 15%, which could be considered less impressive at first sight. Interpretation of the response rate requires a closer look at the data, particularly the mutational spectrum. Preclinical data clearly indicate that the low relative affinity of the first-generation ALKi, crizotinib, would not sufficiently inhibit most point mutations, other than the Arg1275Gln mutation, at concentrations achievable in patients (4). Indeed, this prediction was confirmed by the fact that none of the six neuroblastomas harboring mutations other than the Arg1275Gln mutation showed any response. Focusing only on patients with neuroblastomas harboring the Arg1275Gln mutation, the response rate becomes more interesting. Of the 12 patients with neuroblastomas harboring the Arg1275Gln mutation, 1 patient had a complete response, and 2 patients had a partial response, resulting in an objective response rate of 25%. In a phase II monotherapy trial, this is an activity signal and clinical proof of principle, which warrants further development of ALKi therapy for neuroblastoma. On the basis of preclinical data, the lack of response in patients with ALK amplifications is unexpected, and cannot be explained by the binding affinity of crizotinib to wildtype ALK. However, the observation could be due to the small numbers (only 2 patients with ALK-amplified tumors), or if real, the extremely high ALK expression or aggressiveness of tumors (as ALK amplification is often correlated with amplification of the MYCN oncogene).

In results previously reported for ADVL0912 phase I, two complete remissions were observed in patients with neuroblastoma, with 1 patient reported to have an Arg1275Gln germline mutation (no information was available for ALK mutational status in the other patients; ref. 2). This raised the question, whether only neuroblastomas in patients with germline ALK mutations would be hypersensitive to ALK inhibition. With the current data from Foster and colleagues (1) reporting a complete response in a patient with a somatic mutation, this hypothesis can now be discarded.

It is still remarkable that some neuroblastomas appear to be hypersensitive to ALK inhibition (two reported in the previous report by Mosse and colleagues, and one reported in the current study by Foster and colleagues), similar to the responses observed in most (pediatric) tumors harboring ALK fusion genes. It will be of utmost importance, to take this bedside observation back to the bench, and compare the tumor biology of complete responders with those of other neuroblastomas. A thorough analysis could not only establish markers to diagnostically discriminate between responsive and nonresponsive neuroblastomas upfront, but could point toward targeted combinatorial therapies to render nonresponders into responders.

While the relevance of the study by Foster and colleagues (1) to provide clinical proof of principle that ALK-inhibitory therapy is effective against neuroblastoma cannot be underestimated, crizotinib will not be the ALKi to be further developed for neuroblastoma, due to its lack of efficacy against most ALK mutations arising in neuroblastomas. With the development of second- and third-generation ALKis capable of inhibiting ALK mutations other than Arg1275Gln, clinical research in neuroblastoma will focus on these compounds.

Future clinical and preclinical research will also need to focus on several ALK therapy–related challenges. These include identifying optimal combinatorial therapies, improving diagnostics, and analyzing the significance of subclonal ALK mutations and their implications for therapy. Most importantly, as development of secondary resistance against targeted therapies is almost always observed, it is now the time to conduct research to identify potential mechanisms of resistance (5) and come up with strategies to overcome, or even better, prevent resistance development. Research strategies should not only include preclinical modeling, but should aim to implement initial and subsequent biopsies as well as longitudinal ALK analyses in liquid biopsies in future clinical trials to collect the material required to most efficiently analyze resistance development and determinants of response.

Overall, introducing ALK-inhibitory therapy into treatment of patients with ALK-positive neuroblastomas is a prime example of relatively rapid translation from bench to bedside (Fig. 1). Only 1.5 years after the discovery of ALK mutations in neuroblastomas, the ADVL0912 trial started to recruit patients with relapsed or refractory neuroblastoma to be treated with the ALKi, crizotinib. Subsequently, crizotinib was introduced into first-line neuroblastoma therapy within the ANBL1531 trial. In parallel, second- and third-generation ALKis have been tested in phase I/II trials, and ANBL1531 will be amended to replace crizotinib by the third-generation ALKi, lorlatinib. In an internationally coordinated effort, the SIOPEN HR-NBL2 trial for first-line treatment of high-risk neuroblastoma will be amended to introduce lorlatinib, and a design has been chosen to later perform meta-analysis of data from the ANBL1531 and HR-NBL2 trials. While the availability of ALKis developed for adult malignancies could be considered favorable conditions, the rapid translation also reflects efficient collaborations and a well-planned overall strategy within the worldwide neuroblastoma community. Mosse, who initially codiscovered ALK mutations in neuroblastomas simultaneously with several other international colleagues, subsequently performed most relevant preclinical work, led the first early clinical trials and is now spearheading introduction of the third-generation ALKi, lorlatinib, into first-line therapy for patients with ALK-positive neuroblastomas. The preclinical and clinical development of ALKis can be considered as a blueprint for successful translational research contributed by researchers in academia.

Figure 1.

Overview of the translational timeline from discovery of ALK-activating alterations and preclinical research in neuroblastoma (NB) into ALKi treatment in patients with neuroblastoma. Orange indicates clinical trial with first-generation ALKi. Green indicates clinical trial with second- or third-generation ALKi. ADVL0912 (NCT00939770): first-generation ALKi, crizotinib, relapse/refractory neuroblastoma. CLDK378X2103 (NCT01742286): second-generation ALKi ceritinib, relapse/refractory neuroblastoma. NANT2015-02 (NCT03107988): third-generation ALKi lorlatinib, relapse/refractory neuroblastoma. ANBL1531 (NCT03126916): first-generation ALKi, crizotinib, which was subsequently replaced by third-generation ALKi, lorlatinib, via amendment, first-line therapy. HRNBL2 (NCT04221035): third-generation ALKi, lorlatinib, introduced in ongoing trial via amendment, first-line therapy.

Figure 1.

Overview of the translational timeline from discovery of ALK-activating alterations and preclinical research in neuroblastoma (NB) into ALKi treatment in patients with neuroblastoma. Orange indicates clinical trial with first-generation ALKi. Green indicates clinical trial with second- or third-generation ALKi. ADVL0912 (NCT00939770): first-generation ALKi, crizotinib, relapse/refractory neuroblastoma. CLDK378X2103 (NCT01742286): second-generation ALKi ceritinib, relapse/refractory neuroblastoma. NANT2015-02 (NCT03107988): third-generation ALKi lorlatinib, relapse/refractory neuroblastoma. ANBL1531 (NCT03126916): first-generation ALKi, crizotinib, which was subsequently replaced by third-generation ALKi, lorlatinib, via amendment, first-line therapy. HRNBL2 (NCT04221035): third-generation ALKi, lorlatinib, introduced in ongoing trial via amendment, first-line therapy.

Close modal

No disclosures were reported.

1.
Foster
JH
,
Voss
SD
,
Hall
D
,
Minard
CG
,
Balis
FM
,
Wilner
K
, et al
Activity of crizotinib in patients with ALK-aberrant relapsed/refractory neuroblastoma: a Children's Oncology Group Study (ADVL0912)
.
Clin Cancer Res
2021
;
27
:
3543
8
.
2.
Mossé
YP
,
Lim
MS
,
Voss
SD
,
Wilner
K
,
Ruffner
K
,
Laliberte
J
, et al
Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: a Children's Oncology Group phase 1 consortium study
.
Lancet Oncol
2013
;
14
:
472
80
.
3.
Mosse
YP
,
Laudenslager
M
,
Longo
L
,
Cole
KA
,
Wood
A
,
Attiyeh
EF
, et al
Identification of ALK as a major familial neuroblastoma predisposition gene
.
Nature
2008
;
455
:
930
5
.
4.
Bresler
SC
,
Wood
AC
,
Haglund
EA
,
Courtright
J
,
Belcastro
LT
,
Plegaria
JS
, et al
Differential inhibitor sensitivity of anaplastic lymphoma kinase variants found in neuroblastoma
.
Sci Transl Med
2011
;
3
:
108ra14
.
5.
Debruyne
DN
,
Dries
R
,
Sengupta
S
,
Seruggia
D
,
Gao
Y
,
Sharma
B
, et al
BORIS promotes chromatin regulatory interactions in treatment-resistant cancer cells
.
Nature
2019
;
572
:
676
80
.