<p>Efficacy and Resistance of ALK Inhibitors in Two Inflammatory Myofibroblastic Tumor Patients with ALK Fusions Assessed by Whole Exome and RNA Sequencing</p>

Abstract

We report two inflammatory myofibroblastic tumor (IMT) patients with ALK fusions (RRBP-ALK and TNS1-ALK, respectively). They both received tumor resection surgery and treatment with ALK inhibitors crizotinib followed by alectinib, and upon receiving each of the drugs, showed a brief response, then experienced recurrence or progression of the disease. During the treatment, whole exome sequencing (WES) and RNA sequencing (RNA-Seq) were applied to monitor potential drug-induced gene mutation and expression changes. A novel, secondary mutation in ALK exon 23 (L1196Q) was identified in patient 1 after alectinib resistance developed. Guided by this result, a newer ALK inhibitor, ceritinib was prescribed. The patient was able to achieve a partial response (PR) and is in good condition as of the manuscript date. On the contrary, there was no secondary mutation identified in ALK in patient 2 after drug resistance. While the expression of PTCH1, a negative regulator of the sonic hedgehog (SHH) signaling pathway, was significantly reduced at the time after the treatment with crizotinib before that of alectinib. The expression of PTCH1 was also reduced after the treatment with alectinib. It was reported that ALK can exert its biological functions partially by activating SHH signaling pathway. The down-regulation of PTCH1 suggests the compensatory activation of SHH pathway may cause resistance to ALK inhibitors in IMT. Going forward, monitoring gene mutation and expression changes through DNA and RNA sequencing will be able to offer opportunities to investigate potential mechanisms of drug resistance and will help to achieve precise prescription for better treatment outcomes.

Crizotinib in Sarcomatous Malignancies Harboring ALK Fusion With a Definitive Partner(s): Response and Efficacy

“…One IMT case with FN1 partner mutation had no response to crizotinib, but the tumor dramatically shrunk following lorlatinib neoadjuvant treatment followed by radical resection ( 28 ). Another IMT case with a TNS1 partner progressed shortly after the crizotinib response and died upon switching to alectinib ( 30 ). Three pediatric cases (cases 21, 22, 19) were off crizotinib upon achieving no evidence of disease (NED) or stable disease (SD), with recurrent lesions surgically removed, hence achieving long-term survival ( 23 ).…”

“…As shown in Table 4 , crizotinib-related AEs were observed in 16 cases, with some cases having multiple AEs ( 4 , 7 , 13 , 18 , 22 ). Serious AEs, including transaminitis, neutropenia, renal cyst, cellulitis, and multiple fractures, were seen in 7 cases prompting crizotinib cessation or dose reduction ( 1 , 7 , 18 , 20 , 23 , 29 , 30 ). Fatal AEs in 2 cases led to death, which occurred in 0.5 and 4ms, respectively, after crizotinib initiation.…”

“…Ten cases had no response or progressed on crizotinib treatment ( 11 , 13 , 15 , 23 , 24 , 28 , 30 , 32 ). Nine of them received next-generation ALK inhibitors (ceritinib, brigatinib, alectinib, or lorlatinib) with 77.8% (7/9) achieving ORR ( 11 , 13 , 23 , 24 , 28 , 30 , 32 ), and the remaining two cases resistant to ceritinib or alectinib died within one year after their progression on crizotinib ( 23 , 30 ). One case with radical surgery followed by alectinib adjuvant treatment was still alive without evidence of disease ( 15 ).…”

“…One case with radical surgery followed by alectinib adjuvant treatment was still alive without evidence of disease ( 15 ). Two cases showed no response to alectinib but achieved tumor shrinkage following subsequent ceritinib treatment ( 24 , 30 ).…”

“…Second generation of ALK TKIs, including ceritinib, brigatinib, alectinib, were usually effective in later lines ( 13 , 32 ), similar to their current indications in NSCLC. Interestingly, 2 cases that progressed on alectinib following crizotinib resistance showed response to subsequent ceritinib ( 24 , 30 ). Different ALK inhibitors bind slightly differently within the ATP-binding pocket of the ALK kinase domain, and thus coax different resistance mutation patterns.…”