Game changers in pediatric cancer

One of the first chromosomal rearrangements linked to cancer, BCR-ABL1 – more commonly known as the Philadelphia chromosome – results in aberrant activation of the ABL1 kinase. It is present in nearly all cases of chronic myeloid leukemia (CML) and 3% to 5% of patients with ALL, and thus became the central focus of targeted drug development. Imatinib was initially approved by the US Food and Drug Administration (FDA) in 2001 for the treatment of adult patients with CML and had such a significant impact on the treatment landscape that it made the cover of Time magazine as a “magic bullet” in the war on cancer.⁸

Approval was expanded into pediatric patients in 2006 and for pediatric patients with ALL in 2013. However, as with the use of most kinase inhibitors, tumors can evolve under the selective pressure of treatment, developing additional molecular abnormalities that drive resistance.⁹

Next-generation multikinase inhibitors that more potently inhibit the BCR-ABL1 fusion protein have been developed to provide additional treatment options for patients who become resistant to imatinib. Dasatinib and nilotinib are among several drugs that have recently been approved for pediatric cancer therapy (Table 1). Both therapies were approved to treat children with Philadelphia chromosome-positive CML in the chronic phase in either the front- or second-line setting after failure of imatinib.

The approval of dasatinib was based on data from 97 patients across 2 trials, 51 of whom were newly diagnosed and 46 previously treated with imatinib. Most of the patients were treated with dasatinib 60 mg/m² once daily. After 2 years of follow-up, more than 95% of newly diagnosed patients and 82.6% of relapsed/refractory patients had complete cytogenetic response.¹⁰

Nilotinib was approved on the basis of findings from 2 clinical trials including 69 patients – 1 trial involving patients who were refractory to or relapsed after dasatinib and imatinib treatment, and 1 that included both relapsed/refractory and newly diagnosed patients. Patients received nilotinib 230 mg/m² twice daily, rounded to the nearest 50-mg dose, in 28-day cycles. By cycle 12, the cumulative major molecular response rate (MMR) was 47.7% in patients with relapsed/refractory disease, and 64% in newly diagnosed patients.¹¹ Clinical trials of both drugs in the pediatric setting are ongoing.
 

Other prominent gene fusions

Gene fusions involving the anaplastic lymphoma kinase (ALK) occur in patients with non–small-cell lung cancer and ALK inhibitors have provided an effective new treatment option for patients whose tumors display this abnormality.

ALK fusions are also a prominent feature of several kinds of pediatric cancers and ALK inhibitors offer promise in this setting.^7,12 An NPM-ALK fusion is found in 90% of pediatric anaplastic large cell lymphoma (ALCL) cases,¹³ whereas a variety of ALK fusions are found in up to half of patients with inflammatory myofibroblastic tumor (IMT), a rare form of soft tissue sarcoma.¹⁴ ALK inhibitors are being tested in a variety of clinical trials in pediatric patients (Table 2).

The results of a small phase 1 study of crizotinib in pediatric patients with ALK-positive ALCL (n = 26) or IMT (n = 14) were recently published. ALCL patients received crizotinib at a dose of 165 mg/m², while IMT patients were given 100, 165, or 280 mg/m². For the latter, the results were presented as a pooled cohort since safety and efficacy data were similar across dose levels. The overall response rate (ORR) was 83% for patients with ALCL and 86% for those with IMT. Grade 3/4 adverse events occurred in 83% and 71% of patients, respectively, and most commonly involved reduced neutrophil count.¹⁵

Most recently and perhaps most promisingly, fusions involving the neurotrophic tropomyosin receptor kinase (NTRK) gene have generated significant buzz. There are 3 NTRK genes, NTRK1, 2, and 3, which encode the TRKA, TRKB, and TRKC proteins, respectively.

To date, 22 different partner genes have been identified that can fuse with the NTRK genes and, as with other kinase fusions, drive constitutive activation of the receptor proteins and downstream oncogenic signaling pathways, including the mitogen-activated protein kinase (MAPK) pathway (Figure 2).

NTRK fusions are being identified in an ever-growing number of cancer types, but are typically found in a small percentage of patients. However, in certain rare pediatric tumors, including congenital infantile fibrosarcoma and papillary thyroid cancer, they are found at much higher frequencies.

TRK inhibitors have been developed to target the fusion proteins and, given the spread of NTRK fusions across different types of cancers, they offer the most substantial promise as the next tumor agnostic cancer therapy – to treat patients based on the shared presence of a molecular aberration, irrespective of the type of cancer.¹⁶

The ongoing SCOUT trial is evaluating larotrectinib (LOXO-101) in pediatric patients. Among 24 patients (17 with NTRK fusions and 7 without) with infantile fibrosarcoma (47%), soft tissue sarcoma (41%) or papillary thyroid cancer (12%), the ORR was 93%, including complete response (CR) in 13% of patients.¹⁷

Preliminary results from an ongoing phase 1/2 study of entrectinib in pediatric patients with extracranial solid tumors were also recently presented at the annual meeting of the American Society for Clinical Oncology (ASCO). Among 15 evaluable patients enrolled to date, 3 have NTRK fusions and all experienced an objective response, with 1 (a patient with IMT) ongoing at 10 months.¹⁸