Table 4.
Examples of studies and cases of targeted therapies in ALK-altered cancers (other than NSCLC) (See Supplemental Table 1 for NSCLC studies).
| Tumor characteristics (No. of patients) Study Title | ALK alteration | Type/Phase of study | Drug | CR/PR (N/total N (%)) | Comment | References/CT.gov ID number if ongoing |
|---|---|---|---|---|---|---|
|
ALCL (N = 16) A8081013 (NCT01121588) PROFILE 1013 |
NPM1-ALK fusion | Phase IB study in non-NSCLC tumor | Crizotinib | 9/16 (56%) | 132 | |
|
ALCL (N = 26) ADVL0912 (NCT00939770) |
NPM1-ALK fusion | Phase I/II | Crizotinib |
ALCL165 group: 5/6 (83%) ALCL280 group: 18/20 (90%) |
ALCL cases treated at doses of 165 mg/m2 (ALCL165) and 280 (ALCL280) mg/m2 | 130 |
| ALCL (N = 10 in ALCL cohort) | NPM1-ALK fusion | Phase II | Alectinib | 8/10 (80%) | 35 | |
| Colon cancer (N = 1) | CAD-ALK fusion | Case report |
Entrectinib ALKA-372-001 phase I study |
1/1(100%) | DOR 4+ months | 48 |
| Colon cancer (N = 1) | EML4-ALK fusion (E21; A20) and | Case report |
Crizotinib Alectinib Lorlatinib |
1/1(100%) |
Patient was treated with crizotinb, and had a PR, Developed leptomeningeal disease switched to alectinib for few weeks and then lorlatinib; had PR with latter and DOR was 11 months |
141 |
| DLBCL (N = 2) | ALK fusion partner unknown | Case series | Crizotinib | 1/2 (50%) | 133 | |
| Erdheim-Chester disease (non-Langherhans histicocytosis) (N = 1) | ALK-KIF4B | Case report | Alectinib | 1/1(100%) | DOR 6+ months | Included in this manuscript |
| Glioma, high grade (N = 1) | SPECC1L–ALK fusion | Case report | Lorlatinib |
1/1 (100%) 3 y/o boy |
146 | |
| Histiocytosis with ALK fusions (N = 11) |
KIF5B-ALK fusion (N = 10) DCTN1-ALK fusion (N = 1) |
Retrospective study |
Crizotinib Alectinib Brigatinib Lorlatinib Ceritinib |
11/11(100%) | Median time on ALK inhibitors 16 months (range 3-43 months) | 74 |
|
Inflammatory myofibroblastic sarcoma (EIMS) (epithelioid) (N = 1) |
PRRC2B-ALK fusion | Case report |
Crizotinib Alectinib Ceritinib Lorlatinib |
1/1 (100%) | Patient was treated with four sequential ALK inhibitors and had PR to first three ALK Inhibitors | 142 |
| IMT (N = 14 pediatric patients.) (NCT00939770) | NPM-ALK fusion | Phase I/II | Crizotinib | 12/14 (86%) | Circulating tumor-derived NPM-ALK transcript decreased with response. | 130 |
| IMT (N = 2) | Usually bear ALK fusions | Case series | Brigatinib | 1/2 (50%) | 134 | |
| IMT of head and neck (N = 1 | SQSTM1-ALK fusion gene | Case report | Alectinib | 1/1 (100%) | DOR 17+ months | 135 |
| Mesothelioma (peritoneal) | STRN-ALK Fusion | Case report | Ceritinib | 1/1(100%) | DOR 3+mths | 144 |
| Multiple myeloma, non-secretory (N = 1) Myeloma | TFG-ALK fusion | Case report | Alectinib | 1/1(100%) | DOR 24+months | 73 |
| Neuroblastoma (N = 1) | ALK mutation at exon 24 F1245C | Case report | Alectinib | 1/1 (100 %) | DOR 12+ months | 136 |
|
Neuroblastoma (N = 28) A New Approaches to Neuroblastoma Consortium study |
ALK mutations/amplifications | Phase I | Lorlatinib |
In (2–17) age group, 1/18 (5%) In (15–50) age group, 4/10 (40%) |
148 | |
| Ovarian Cancer (Refractory high-grade serous) [N = 1] | EML4-ALK Fusion | Case report | Alectinib | 1/1(100%) | 147 | |
| Pancreatic adenocarcinoma (N = 1) | PPFIBP1-ALK fusion | Case report |
Alectinib/ Lorlatinib |
Minor response with alectinib lasted for 5 months.Pt. achieved stable disease for 2 months on lorlatinb | 94 | |
| Pancreatic adenocarcinoma (N = 1) | EML4-ALK fusion | Case report |
Crizotinib Alectinib |
1/1 (100%) to both crizotinib and alectinib |
PFS with crizotinib, 8 months PFS with alectinib 10 months |
137 |
| Pancreatic neuroendocrine cancer (N = 1) | KANK1-ALK Fusion | Case report | Lorlatinb | 1/1 (100%) | DOR 4+ months | 149 |
| Prostate cancer (N = 1) | ALK F1174C-activating point mutation | Case | Alectinib | Stable disease >6mths | 85 | |
| Renal cell carcinoma (N = 1) | VCL-ALK fusion | Case report |
Entrectinib ALKA-372-001 and STARTRK-1 phase I study |
1/1(100%) | 126 | |
| Thyroid cancer, medullary (N = 1) | CCDC6-ALK fusion | Case report | Crizotinib/Alectinib | 1/1(100%) | 139 | |
| Thyroid cancer, anaplastic (N = 1) | STRN-ALK fusion | Case report | Ceritinib /Brigatinib | 1/1(100%) | DOR 15+ months | 138 |
| Studies with multiple tumor types | ||||||
|
ALK-altered tumors such as ALCL [N = 1], IMT [N = 4], GBM, N = 12] and others [N = 5]) ≥1 prior systemic therapy ASCEND 10 study. (NCT02465528) |
Type of alterations not reported. But IMT and ALCL usually bear fusions..GBM generally have non-fusion ALK alterations such as overexpression) | Phase II | Ceritinib |
ALCL 1/1(100%) IMT 3/4 (75%) Glioblastoma 0/12 (0%) |
140 | |
|
Neuroblastoma (N = 11) Children’s Oncology Group consortium study of 79 pts. (including neuroblastoma, IMT, NSCLC and ALCL) |
ALK rearrangements seen in ALCL and IMT ALK mutations seen in neuroblastoma. Arg1275 Gln (patient with CR) |
Phase I/II | Crizotinib | Neuroblastoma 1/11(9%) | 131 | |
|
NCI match subgroup F Colorectal carcinoma [N = 2] Carcinoma of unknown primary [N = 1] Leiomyosarcoma [N = 1] (NCT02465060) |
EML4-ALK STRN-ALK ACTG2-ALK fusions |
Phase II | Crizotinib | 2/4 (50%) | CR in leiomyosarcoma and PR in colorectal | 145 |
| Ongoing studies | ||||||
| Plasmablastic ALK-altered large B cell lymphoma. | Phase II | Belantomab Mafodotin | NCT04676360 | |||
| ALK-positive relapsed/refractory Neuroblastoma | Phase I/II | Ceritinib+ Ribocicliib | NCT02780128 | |||
| ANBL1531: Children with Newly Diagnosed High-Risk Neuroblastoma | Phase III | 131I-Metaiodobenzylguanidine (131I-MIBG) or Crizotinib Added to Intensive Therapy | NCT03126916 | |||
| Relapsed ALK-positive lymphoma previously treated With ALK Inhibitors | Phase II | Lorlatinib | NCT03505554 | |||
| ANHL12P1: newly diagnosed Stage II-IV ALCL | Phase II | Brentuximab Vedotin or Crizotinib in Combination with Chemotherapy | Results available for the Brentuximab arb | NCT01979536 | ||
| HR-NBL2: High-Risk Neuroblastoma Study of SIOP-Europe-Neuroblastoma (SIOPEN) | Phase II | Lorlatinib | NCT04221035 | |||
| NANT 2015-02: ALK-driven Relapsed or Refractory Neuroblastoma Phase I | Phase I | Lorlatinib | NCT03107988 | |||
| Relapsing/Refractory ALK-altered Anaplastic Large Cell Lymphoma | Phase II | Nivolumab | Evaluation of response in patients with progressive disease (Cohort 1) or as consolidative immunotherapy in patients in complete remission after relapse (Cohort 2) | NCT03703050 | ||
| ALK-altered ALCL, IMT or Other Solid Tumors (Briga-PED) | Phase I/II | Brigatinib | Phase I dose escalation in ALK-altered ALCL or ALK-altered solid tumors. Phase II Cohort B1: ALK-altered IMT Cohort B2: ALK-altered ALCL | NCT04925609 | ||
| ALK Fusion-positive Solid or CNS Tumors (prior treatment has proven to be ineffective or from whom there is no curative standard treatment available) | Phase I/II | Alectinib | NCT04774718 | |||
| Solid Tumors Harboring ALK, ROS1, or NTRK1-3 Rearrangements (TRIDENT-1) | Phase I/II | Repotrectinib | NCT03093116 | |||
|
Solid tumors harboring NTRK 1/2/3 (Trk A/B/C), ROS1, or ALK gene rearrangements (Fusions) (STARTRK-2) Phase I/II |
Phase I/II | Entrectinib | NCT02568267 | |||
| Relapsed or refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders with ALK or ROS1 Genomic Alterations (A Pediatric MATCH Treatment Trial) | Phase II | Ensartinib | NCT03213652 | |||
| Malignant Melanoma with ALK alterations | Phase II | Ensartinib | NCT 03420508 | |||
| Patients with Advanced NSCLC and Other Solid Tumors Harboring ALK Rearrangement or Activating ALK Mutation (ALKOVE-1) | Phase I/II | NVL-655 | NCT05384626 | |||
Abbreviations: ACTG2 Actin Gamma 2, Smooth Muscle, ALCL anaplastic large cell lymphoma, CAD carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase, CCDC6 Coiled-Coil Domain Containing 6, CR complete response, DCTN1 dynactin, DLBCL diffuse large B cell lymphoma, DOR duration of response, EML4 echinoderm microtubule-associated protein like-4, GBM glioblastoma multiforme, GOPC Golgi Associated PDZ And Coiled-Coil Motif Containing, IMT inflammatory myofibroblastic tumor, KANK1 KN Motif And Ankyrin Repeat Domains 1, KIF4B/5B kinesin family member 4B/5B, NA not available, NPM1 nucleophosmin1, NSCLC non-small cell lung cancer, PFS progression free survival, PR partial response, PPFBP1 PPFIA Binding Protein 1, PRRC2B proline rich coiled-coil 2B, SD stable disease, SPECC1L sperm antigen with calponin homology and coiled-coil domains 1 like, SQSTM1 sequestosome 1, STRN striatin, TFG TRK-fused gene, VCL vinculin.