ALK Inhibitors in Patients With ALK Fusion–Positive GI Cancers: An International Data Set and a Molecular Case Series

Abstract

PURPOSE In GI cancers, anaplastic lymphoma kinase ( ALK) rearrangements are extremely less frequent than in non–small-cell lung cancer but may be important to offer personalized strategies of treatment in selected patients. Data about the activity and efficacy of ALK inhibitors (ALKi) in GI cancers are scarce. MATERIALS AND METHODS We assembled a clinical and molecular international data set of pretreated patients with metastatic or nonresectable cancers of GI primary tumor origin with documented ALK rearrangement treated with at least one line of ALKi. Measurable disease as per RECIST 1.1 was required for response analysis. RESULTS Primary tumor sites were distributed as follows: 5 (38%) pancreas, 3 (23%) right colon, and 1 (8%) for each one of gastric, duodenal, rectal, left colon, and biliary tract sites. Seven patients (54%) were treated with alectinib, 5 (38%) with crizotinib, and 1 (8%) with entrectinib. After disease progression, five patients (38%) received a subsequent ALKi treatment line, and at the time of data cutoff date, treatment was still ongoing in two patients. Five of 12 evaluable patients (41%) achieved a partial response to first-line ALKi, five patients (41%) had stable disease, and 2 (17%) had progressive disease. No complete responses were registered. At a median follow-up of 39.6 months (interquartile range: 19.8-59.5), the median progression-free survival was 5.0 months (95% CI, 3.68 to no response) and the median overall survival was 9.3 months (95% CI, 5.46 to no response). CONCLUSION Treatment with ALKi provides remarkable responses and clinical benefit in pretreated patients with ALK fusion–positive GI malignancies. Despite the rarity, ALK rearrangements represent an important therapeutic target in individual pretreated patients with GI solid tumors. Further work providing prospective clinical validation of this target is needed.

Emerging Role of Targeted Therapy in Metastatic Pancreatic Adenocarcinoma

“…A case series of KRAS WT metastatic PDAC harboring ALK rearrangements described four patients who benefitted from ALK -directed therapy, with two of these patients being on therapy for over 1 year [ 83 ]. In a separate case series, five patients with KRAS WT PDAC harboring ALK rearrangements received ALK -directed therapy [ 84 ]. In this case series, a response to therapy was seen in one PDAC patient treated with crizotinib and one PDAC patient treated with alectinib [ 84 ].…”

“…In a separate case series, five patients with KRAS WT PDAC harboring ALK rearrangements received ALK -directed therapy [ 84 ]. In this case series, a response to therapy was seen in one PDAC patient treated with crizotinib and one PDAC patient treated with alectinib [ 84 ]. Treatment with ALK inhibitors is generally well-tolerated, although gastrointestinal and pulmonary toxicities have been reported [ 78 , 82 , 85 ].…”

Targeting Anaplastic Lymphoma Kinase in GI Primary Malignancies

“…27 Although novel research continues to evaluate the feasibility of computer algorithms to determine the optimal drug combinations while taking tumor heterogeneity into account, 72 others question the utility of liquid biopsy in sequencing tumor DNA from different metastasis and capturing tumor heterogeneity and charting clonal evolution during treatment. 73 An interesting observation seen in the companion to this article by Ambrosini et al 44 was that liquid biopsy in a patient detected an ALK resistance mutation that was not seen on lymph node NGS, and captured depletion of specific clonal populations during treatment.…”

“…[52][53][54][55][56] Therefore, sequencing of therapy, incorporation of immunotherapy, and the utility of second-line ALKi after progression on an ALKi are important questions for future research. The article that accompanies this editorial by Ambrosini et al 44 does shed some light in this space, where second-line ALKi therapy resulted in disease control in all five patients who underwent treatment. Although these data demonstrate promising clinical activity for ALKi in ALKpositive GI cancers, given the retrospective study design and varied ALKi usage, a well-designed prospective basket trial may need to be conducted to allow tissueagnostic regulatory approval for this indication, similar to other rare genomic oncogenic driver aberrancies such as NTRK for larotrectinib and entrectinib.…”

“…In these circumstances, realworld clinical data provide the first level of evidence of the therapeutic implications of these rarer targettable genomic aberrancies. Ambrosini et al 44 presents a collection of patients with ALK-positive GI cancers with treatment data associated with carefully annotated clinical data, lending credence to ALK being an important oncogenic driver in GI cancer. The international, multicenter analysis of 13 patients was derived from both published retrospective series and unpublished cases, comprising metastatic or locally advanced unresectable GI cancers of any primary site.…”