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| Gene | EML4 ALK |
| Variant | EML4 - ALK |
| Impact List | fusion |
| Protein Effect | gain of function |
| Gene Variant Descriptions | EML4-ALK results from the fusion of EML4 and ALK, resulting in constitutive kinase activity, transformation in cultured cells, and tumor formation in mouse models (PMID: 19064915, PMID: 17625570, PMID: 35138907). EML4-ALK fusions have been associated with non-small cell lung cancer (PMID: 26755435). |
| Associated Drug Resistance | |
| Category Variants Paths |
ALK mutant ALK act mut EML4 - ALK ALK mutant ALK rearrange ALK fusion EML4 - ALK EML4 mutant EML4 fusion EML4 - ALK |
| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| ALK fusion | Erdheim-Chester disease | sensitive | Alectinib | Guideline | Actionable | Alecensa (alectinib) is included in guidelines as first-line or subsequent-line therapy for patients with Erdheim-Chester disease harboring ALK fusions (NCCN.org). | detail... |
| ALK fusion | Erdheim-Chester disease | sensitive | Ceritinib | Guideline | Actionable | Zykadia (ceritinib) is included in guidelines as first-line or subsequent-line therapy for patients with Erdheim-Chester disease harboring ALK fusions (NCCN.org). | detail... |
| ALK fusion | Erdheim-Chester disease | sensitive | Lorlatinib | Guideline | Actionable | Lorbrena (lorlatinib) is included in guidelines as first-line or subsequent-line therapy for patients with Erdheim-Chester disease harboring ALK fusions (NCCN.org). | detail... |
| ALK fusion | Advanced Solid Tumor | sensitive | Entrectinib | Case Reports/Case Series | Actionable | In a Phase I/II trial (STARTRK-NG), Rozlytrek (entrectinib) treatment was safe and resulted in an overall response rate (ORR) of 57.7% (15/26, 7 complete responses) with median duration of response and progression-free survival not reached in pediatric patients with CNS or extracranial solid tumors harboring fusions in NTRK1, NTRK2, NTRK3, ROS1, or ALK, ORR was 33.3% (1/3) in patients harboring ALK fusions (PMID: 35395680; NCT02650401). | 35395680 |
| ALK fusion | lung non-small cell carcinoma | sensitive | TQ-B3139 | Phase I | Actionable | In a Phase I trial, TQ-B3139 (CT-711) treatment demonstrated safety and resulted in an overall response rate (ORR) of 61.9% (39/63), an intracranial ORR of 70% (7/10), disease control rate of 84.1% (53/63), and median progression-free survival (PFS) of 19.0 months in patients with non-small cell lung cancer harboring an ALK fusion or ROS1 fusion, with TKI-naive patients demonstrating a longer PFS (25.2 mo vs 5.4 mo, p=0.02) (PMID: 35940055; NCT03099330). | 35940055 |
| ALK fusion | lung adenocarcinoma | predicted - sensitive | Lorlatinib | Case Reports/Case Series | Actionable | In a clinical case study, Lorbrena (lorlatinib) treatment resulted in reduction of the brain metastases in a patient with ALK-positive lung adenocarcinoma who had been previously treated with Alecensa (alectinib) and Xalkori (crizotinib) (PMID: 35373538). | 35373538 |
| ALK fusion | lung non-small cell carcinoma | sensitive | Ceritinib | FDA approved - On Companion Diagnostic | Actionable | In a Phase I trial that supported FDA approval, Zykadia (ceritinib) resulted in a blinded independent review committee (BIRC)-assessed objective response rate of 44% (72/163) and a duration of response of 7.1 months in ALK-rearranged non-small cell lung cancer patients (PMID: 25754348; NCT01283516). | detail... detail... 25754348 |
| ALK fusion | Erdheim-Chester disease | sensitive | Crizotinib | Guideline | Actionable | Xalkori (crizotinib) is included in guidelines as first-line or subsequent-line therapy for patients with Erdheim-Chester disease harboring ALK fusions (NCCN.org). | detail... |
| ALK fusion | inflammatory myofibroblastic tumor | sensitive | Crizotinib | FDA approved | Actionable | In a Phase I/II trial (Study ADVL0912) that supported FDA approval, Xalkori (crizotinib) therapy was safe and resulted in an objective response rate of 86% (12/14, 5 complete responses, 7 partial responses) and stable disease in 14% (2/14) of pediatric patients with ALK-positive unresectable inflammatory myofibroblastic tumors, with a median duration of response of 1.63 years (PMID: 28787259; NCT00939770). | detail... 28787259 |
| ALK fusion | inflammatory myofibroblastic tumor | sensitive | Crizotinib | FDA approved | Actionable | In a Phase Ib trial (PROFILE 1013) that supported FDA approval, treatment with Xalkori (crizotinib) resulted in an objective response rate of 66.7% (6/9, 1 complete response, 5 partial responses) and stable disease in 33.3% (3/9) of adult patients with advanced ALK-positive inflammatory myofibroblastic tumors, with a median duration of response of 74.1 weeks in (PMID: 29352732; NCT00939770). | 29352732 detail... |
| ALK fusion | lung non-small cell carcinoma | sensitive | Brigatinib | FDA approved - Has Companion Diagnostic | Actionable | In a Phase II trial (ALTA) that supported FDA approval, Alunbrig (brigatinib) treatment resulted in an overall response rate of 45% (51/112) in the 90mg arm and 54% (59/110) in the 180mg arm, and median progression-free survival of 9.2 and 11.0 months respectively, in ALK-rearranged (fusion) non-small cell lung carcinoma patients who progressed on Xalkori (crizotinib) (PMID: 28475456; NCT02094573). | 28475456 detail... |
| ALK fusion | lung non-small cell carcinoma | sensitive | Brigatinib | Phase Ib/II | Actionable | In a phase I/II clinical trial, Alunbrig (brigatinib) was determined to be safe and efficacious in patients with advanced, ALK-fusion positive NSCLC (PMID: 24091716). | 24091716 |
| ALK fusion | lung non-small cell carcinoma | sensitive | Brigatinib | FDA approved - Has Companion Diagnostic | Actionable | In a Phase III trial (ALTA-1L) that supported FDA approval, Alunbrig (brigatinib) treatment resulted in superior progression-free survival (HR=0.49, p=0.0007) compared to Xalkori (crizotinib) in patients with ALK-rearrangement positive metastatic non-small cell lung cancer (Ann Oncol., Apr 2019, 30 (Suppl 2):ii48; NCT02737501). | detail... detail... detail... |
| ALK fusion | anaplastic large cell lymphoma | sensitive | Crizotinib | FDA approved | Actionable | In a Phase I/II trial that supported FDA approval, Xalkori (crizotinib) treatment resulted in an objective response rate (ORR) of 83% (5/6, all complete responses (CR)) at the 165 mg dose, and an ORR of 90% (18/20, 16 CR) at the 280 mg dose, in pediatric patients 1 years of age or older and young adults with relapsed or refractory ALK-positive anaplastic large cell lymphoma (PMID: 28787259; NCT00939770). | 28787259 detail... |
| ALK fusion | Advanced Solid Tumor | predicted - sensitive | Alectinib | Phase Ib/II | Actionable | In a Phase I/II trial, Alecensa (alectinib) treatment resulted in 1 complete response, 3 partial responses, and 2 stable diseases in 7 evaluable pediatric patients with advanced solid tumors harboring ALK fusions with TPM3, CLTC, PLEKHA7, DCTN1, or HNRNPA3 (Cancer Res (2024) 84 (7_Supplement): CT039; NCT04774718). | detail... |
| ALK fusion | lung adenocarcinoma | predicted - sensitive | Alectinib | Case Reports/Case Series | Actionable | In a clinical case study, Alecensa (alectinib) treatment resulted in shrinkage of the brain and spinal cord metastases in a patient with ALK-positive lung adenocarcinoma, who had been previously treated with Xalkori (crizotinib) (PMID: 35373538). | 35373538 |
| ALK fusion | lung adenocarcinoma | predicted - sensitive | Alectinib | Case Reports/Case Series | Actionable | In a clinical case study, Alecensa (alectinib) treatment resulted in shrinkage of brain metastases after 6 months in a patient with concomitant ALK fusion-positive lung adenocarcinoma and ERBB2 (HER2)-mutant, hormone receptor-negative invasive ductal carcinoma of the breast (PMID: 37113357). | 37113357 |
| ALK fusion | lung adenocarcinoma | predicted - sensitive | Crizotinib | Case Reports/Case Series | Actionable | In a clinical case study, Xalkori (crizotinib) treatment resulted in reduction of the lung tumors in a patient with metastatic ALK-positive lung adenocarcinoma, however, there was development of new brain metastases (PMID: 35373538). | 35373538 |
| ALK fusion | lung non-small cell carcinoma | sensitive | Ensartinib | Phase II | Actionable | In a Phase II trial, Ensartinib (X-396) treatment resulted in an objective response in 57% (43/75; all partial responses), and stable disease (SD) in 33% (25/75) of patients with crizotinib-refractory non-small cell lung cancer harboring an ALK fusion, with a response rate of 59% and SD rate of 31% in the 70 patients with EML4-ALK, and a response rate of 40% and SD rate of 60% in the 5 patients with non-EML4 ALK fusions (PMID: 31628085; NCT03215693). | 31628085 |
| ALK fusion | Advanced Solid Tumor | predicted - sensitive | Repotrectinib | Phase I | Actionable | In a Phase I (TRIDENT-1) trial, Augtyro (repotrectinib) treatment resulted in stable disease in 25% (4/16) of patient with advanced solid tumor harboring ALK fusions who completed 2 cycles of treatment (J Clin Oncol 36, 2018 (suppl; abstr 2513); NCT03093116). | detail... |
| ALK fusion | lung non-small cell carcinoma | sensitive | Alectinib | Phase III | Actionable | In a Phase III trial, treatment with Alecensa (alectinib) resulted in improved progression-free survival compared to treatment with Xalkori (crizotinib) (HR=0.34) in ALK-positive non-small cell lung cancer patients (J Clin Oncol 34, 2016 (suppl; abstr 9008)). | detail... |
| ALK fusion | lung non-small cell carcinoma | sensitive | Alectinib | Phase II | Actionable | In a Phase II trial, treatment with Alecensa (alectinib) resulted in a 49% (60/122) overall response rate in non-small cell lung cancer patients positive for an ALK fusion who had previously progressed on Xalkori (crizotinib) therapy (J Clin Oncol 33, 2015 (suppl; abstr 8008)) | detail... |
| ALK fusion | lung non-small cell carcinoma | sensitive | Alectinib | FDA approved - On Companion Diagnostic | Actionable | In a Phase III trial supporting FDA approval (ALEX), Alecensa (alectinib) treatment resulted in improved rate of progression-free survival compared to Xalkori (crizotinib) (68.4% vs 48.7%, HR=0.47), and median progression-free survival (25.7 vs 10.4 months) in non-small cell lung cancer patients harboring ALK rearrangements (PMID: 28586279; NCT02075840). | detail... 28586279 detail... |
| ALK fusion | lung non-small cell carcinoma | sensitive | Alectinib | FDA approved - On Companion Diagnostic | Actionable | In a Phase III trial supporting FDA approval (ALINA), adjuvant Alecensa (alectinib) treatment improved 2-year disease-free survival rate (93.8% vs 63.0%, HR 0.24, p<0.001) compared to chemotherapy in patients with resected non-small cell lung cancer harboring ALK fusion, and was associated with CNS disease-free survival benefit (HR 0.22) (PMID: 38598794; NCT03456076). | detail... 38598794 detail... |
| ALK fusion | lung adenocarcinoma | predicted - sensitive | Brigatinib | Case Reports/Case Series | Actionable | In a clinical case study, Alunbrig (brigatinib) treatment resulted in a significant reduction of brain metastases in a patient with lung adenocarcinoma harboring an ALK fusion (PMID: 38158887). | 38158887 |
| ALK fusion | lung non-small cell carcinoma | sensitive | Lorlatinib | FDA approved - On Companion Diagnostic | Actionable | In a Phase II trial that supported FDA approval, Lorbrena (lorlatinib) treatment resulted in an objective response (OR) rate of 47% (93/198; 4 CR, 89 PR) and a median time to overall first tumor response of 1.4 months, and an objective intracranial response rate of 63% (51/81) and median time to first intracranial response of 1.4 months in ALK-positive (rearrangement or fusion) non-small cell lung cancer patients who had received at least one prior ALK inhibitor therapy (PMID: 30413378; NCT01970865). | detail... 30413378 detail... |
| ALK fusion | lung non-small cell carcinoma | sensitive | Lorlatinib | Phase I | Actionable | In a Phase I trial, Lorlatinib (PF-06463922) demonstrated safety and resulted in a 50% (26/52) overall response rate in patients with ALK-positive or ROS1-positive non-small cell lung cancer, including intracranial responses in patients with CNS metastasis (J Clin Oncol 34, 2016 (suppl; abstr 9009)). | detail... |
| ALK fusion | lung non-small cell carcinoma | sensitive | Lorlatinib | Phase III | Actionable | In a Phase III trial (CROWN), Lorbrena (lorlatinib) treatment (n=149) demonstrated superior efficacy compared to Xalkori (crizotinib) (n=147) at 5-year follow-up in ALK-positive (rearrangement or fusion) non-small cell lung cancer patients, with improved median progression-free survival (PFS, not reached vs 9.1 months, HR 0.19), 5-year PFS rate (60% vs 8%), and median time to intracranial progression (not reached vs 16.4 months) (PMID: 38819031; NCT03052608). | 38819031 |
| ALK fusion | lung non-small cell carcinoma | sensitive | Lorlatinib | FDA approved - On Companion Diagnostic | Actionable | In a Phase III trial (Study B7461006) that supported FDA approval, first-line Lorbrena (lorlatinib) treatment resulted in a significantly improved 12-mo progression-free survival rate (78% vs 39%, HR 0.28, p<0.0010) and a response rate of 76% (113/149) vs 58% (85/147) compared to Xalkori (crizotinib) in patients with advanced ALK-positive non-small cell lung cancer, and led to an intracranial response rate of 71% (12/14) vs 23% (3/13) in patients with measurable CNS metastases (PMID: 33207094; NCT03052608). | 33207094 detail... detail... |
| ALK fusion | Erdheim-Chester disease | sensitive | Brigatinib | Guideline | Actionable | Alunbrig (brigatinib) is included in guidelines as first-line or subsequent-line therapy for patients with Erdheim-Chester disease harboring ALK fusions (NCCN.org). | detail... |
| ALK fusion | renal cell carcinoma | predicted - sensitive | Alectinib | Case Reports/Case Series | Actionable | In a clinical case study, Alecensa (alectinib) treatment resulted in a complete radiological response ongoing for at least 12 months in a patient with metastatic renal cell carcinoma harboring an ALK fusion (PMID: 39205743). | 39205743 |
| ALK fusion | lung non-small cell carcinoma | predicted - sensitive | APG-2449 | Phase I | Actionable | In a Phase I trial, APG-2449 treatment was well tolerated and resulted in preliminary efficacy with 4 partial responses among 14 patients with non-small cell lung cancer harboring an ALK fusion who previously progressed on a second-generation ALK inhibitor, 1 intracranial complete response and 3 partial responses among 8 patients with brain metastases, and an overall response rate of 80% and a disease control rate of 100% among 10 TKI-naive patients (J Clin Oncol 40, no. 16_suppl (June 01, 2022) 9071-9071). | detail... |
| ALK fusion | lung non-small cell carcinoma | predicted - sensitive | NVL-655 | Phase I | Actionable | In a Phase I trial (ALKOVE-1), NVL-655 treatment demonstrated activity in patients with ALK-positive non-small cell lung cancer (including patients with ALK fusion with or without secondary ALK mutations), resulting in a response rate of 38% (39/103), a median duration of response (DOR) of 9.2 months, DOR greater than 6 months in 79% of patients, and a response rate of 39% (15/38) at the RP2D dose of 150mg (Ann Oncol (2024) 35 (suppl_2): S802-S803; NCT05384626). | detail... |
| ALK fusion | anaplastic large cell lymphoma | predicted - sensitive | Crizotinib + Cyclophosphamide + Cytarabine + Dexamethasone + Doxorubicin + Etoposide + Ifosfamide + Methotrexate | Phase II | Actionable | In a Phase II trial (ANHL12P1), the addition of Xalkori (crizotinib) to standard chemotherapy prevented disease relapse in pediatric patients with ALK fusion-positive anaplastic large cell lymphoma, with an event-free survival rate of 76.8%, a 2-year overall survival of 95.2%, and a complete response rate among evaluable patients of 91.7% (55/60) after 2 cycles and 98.3% (59/60) after 6 cycles (PMID: 36534942; NCT01979536). | 36534942 |
| ALK fusion | lung non-small cell carcinoma | sensitive | Crizotinib | FDA approved - On Companion Diagnostic | Actionable | In a Phase III trial (PROFILE 1014) that supported FDA approval, Xalkori (crizotinib) treatment resulted in improved progression-free survival (10.9 vs 7.0 months, HR=0.45, p<0.001) and objective response rate (74% vs 45%) relative to chemotherapy in NSCLC patients with ALK rearrangements (PMID: 25470694; NCT01154140). | 25470694 detail... detail... |
| ALK rearrange | inflammatory myofibroblastic tumor | sensitive | Lorlatinib | Guideline | Actionable | Lorbrena (lorlatinib) is included in guidelines as first-line therapy for patients with advanced, recurrent, metastatic, or inoperable inflammatory myofibroblastic tumor harboring ALK translocations (NCCN.org). | detail... |
| ALK rearrange | lung non-small cell carcinoma | predicted - sensitive | PLB1003 | Phase I | Actionable | In a Phase Ia trial, PLB1003 demonstrated safety and preliminary efficacy, resulted in a disease control rate of 86% (12/14, 10 partial response, 2 stable disease) in patients with ALK-rearranged non-small cell lung cancer who progressed on or did not tolerate previous treatment (Journal of Thoracic Oncology, Volume 14, Issue 10, S651). | detail... |
| ALK rearrange | lung non-small cell carcinoma | no benefit | Erlotinib | Guideline | Actionable | EGFR tyrosine kinase inhibitors including Tarceva (erlotinib), Iressa (gefitinib), Gilotrif (afatinib), and Tagrisso (osimertinib) are not indicated for use as subsequent therapy in ALK rearranged non-small cell lung cancer patients who relapsed on Alecensa (alectinib), Xalkori (crizotinib), or Zykadia (ceritinib) (NCCN.org). | detail... |
| ALK rearrange | Cancer of Unknown Primary | sensitive | Ceritinib | Guideline | Actionable | Zykadia (ceritinib) is included in guidelines for patients with cancer of unknown primary harboring ALK rearrangements (PMID: 36563965, PMID: 30285222; ESMO.org). | detail... 30285222 36563965 |
| ALK rearrange | lung non-small cell carcinoma | no benefit | Belizatinib | Phase I | Actionable | In a Phase I trial, treatment with Belizatinib (TSR-011) in ALK inhibitor-naive non-small cell lung cancer patients (n=14) harboring either an ALK mutation, ALK amplification, or an ALK rearrangement resulted in a partial response in 6 patients and stable disease in 8 patients, however, it was determined that the drug resulted in limited efficacy and development of the drug was discontinued (PMID: 31217479; NCT02048488). | 31217479 |
| ALK rearrange | medullary thyroid carcinoma | predicted - sensitive | Crizotinib | Case Reports/Case Series | Actionable | In a Phase Ib trial (PROFILE 1013), Xalkori (crizotinib) therapy resulted in a partial response in a patient with medullary thyroid carcinoma harboring ALK rearrangement with a response duration of 16.1 weeks (PMID: 29352732; NCT00939770). | 29352732 |
| ALK rearrange | inflammatory myofibroblastic tumor | sensitive | Ceritinib | Phase I | Actionable | In a Phase I trial, Zykadia (ceritinib) treatment was well tolerated and resulted in an overall response rate of 70% (7/10; 7 partial responses) and a disease control rate of 80% (8/10) in pediatric patients with inflammatory myofibroblastic tumor harboring ALK rearrangement, with median progression-free survival not reached (PMID: 34780709; NCT01742286). | 34780709 |
| ALK rearrange | inflammatory myofibroblastic tumor | sensitive | Ceritinib | Guideline | Actionable | Zykadia (ceritinib) is included in guidelines as first-line therapy for patients with advanced, recurrent, metastatic, or inoperable inflammatory myofibroblastic tumor harboring ALK translocations (NCCN.org). | detail... |
| ALK rearrange | lung non-small cell carcinoma | no benefit | Crizotinib + Onalespib | Phase II | Actionable | In a Phase II trial, Onalespib (AT13387) and Xalkori (crizotinib) combination treatment did not significantly improve median progression free survival (269 vs 266 days) or objective response rate (55.4%, 38/68 vs 45.3%, 31/68) compared to Xalkori (crizotinib) single treatment in patients with non-small cell lung carcinoma harboring either an ALK mutation or ALK rearrangement (J Clin Oncol 34, 2016 (suppl; abstr 9059); NCT01712217). | detail... |
| ALK rearrange | inflammatory myofibroblastic tumor | sensitive | Crizotinib | Case Reports/Case Series | Actionable | In a clinical case study, Xalkori (crizotinib) treatment resulted in a partial response after 6 months and a complete response in the second year of treatment in an 8-year-old pediatric patient with metastatic inflammatory myofibroblastic tumor harboring an ALK rearrangement, with response ongoing after 5 years of treatment (PMID: 31615346). | 31615346 |
| ALK rearrange | inflammatory myofibroblastic tumor | sensitive | Crizotinib | FDA approved | Actionable | In a Phase I/II trial (Study ADVL0912) that supported FDA approval, Xalkori (crizotinib) therapy was safe and resulted in an objective response rate of 86% (12/14, 5 complete responses, 7 partial responses) and stable disease in 14% (2/14) of pediatric patients with ALK-positive unresectable inflammatory myofibroblastic tumors, with a median duration of response of 1.63 years (PMID: 28787259; NCT00939770). | 28787259 detail... |
| ALK rearrange | inflammatory myofibroblastic tumor | sensitive | Crizotinib | FDA approved | Actionable | In a Phase Ib trial (PROFILE 1013) that supported FDA approval, treatment with Xalkori (crizotinib) resulted in an objective response rate of 66.7% (6/9, 1 complete response, 5 partial responses) and stable disease in 33.3% (3/9) of adult patients with advanced ALK-positive inflammatory myofibroblastic tumors, with a median duration of response of 74.1 weeks in (PMID: 29352732; NCT00939770). | 29352732 detail... |
| ALK rearrange | inflammatory myofibroblastic tumor | sensitive | Crizotinib | Guideline | Actionable | Xalkori (crizotinib) is included in guidelines as first-line therapy for patients with advanced, recurrent, metastatic, or inoperable inflammatory myofibroblastic tumor harboring ALK translocations (NCCN.org). | detail... |
| ALK rearrange | inflammatory myofibroblastic tumor | sensitive | Crizotinib | Case Reports/Case Series | Actionable | In a clinical case study, Xalkori (crizotinib) treatment resulted in a partial response lasting 40 months in a pediatric patient with an ALK-rearranged inflammatory myofibroblastic tumor (PMID: 34036223). | 34036223 |
| ALK rearrange | lung non-small cell carcinoma | sensitive | TQ-B3139 | Phase III | Actionable | In a Phase III trial, TQ-B3139 (CT-711) improved median progression-free survival (24.87 vs 11.60 mo; HR=0.47, p<0.0001), objective response rate (ORR) (81.68% vs 70.68%, p=0.056), and median duration of response (DOR) (25.79 vs 11.14 mo; HR=0.50, p=0.0003) compared to Xalkori (crizotinib) in ALK-rearranged non-small cell lung cancer patients, and also improved CNS ORR (78.95% vs 23.81%) and CNS DOR (25.82 vs 7.39 mo, p=0.0030) in patients with baseline brain lesions (PMID: 37574511; NCT04009317). | 37574511 |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Brigatinib | Clinical Study - Cohort | Actionable | In a retrospective analysis, non-small cell lung cancer patients with brain metastases harboring an ALK rearrangement demonstrated prolonged survival following treatment with the combination of an ALK-targeted tyrosine kinase inhibitor, including Alunbrig (brigatinib), and radiotherapy (PMID: 26438117). | 26438117 |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Brigatinib | Guideline | Actionable | Alunbrig (brigatinib) is included in guidelines for patients with metastatic non-small cell lung cancer harboring an ALK rearrangement (PMID: 30285222; ESMO.org). | detail... 30285222 |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Brigatinib | FDA approved - Has Companion Diagnostic | Actionable | In a Phase III trial (ALTA-1L) that supported FDA approval, Alunbrig (brigatinib) treatment resulted in superior progression-free survival (HR=0.49, p=0.0007) compared to Xalkori (crizotinib) in patients with ALK-rearrangement positive metastatic non-small cell lung cancer (Ann Oncol., Apr 2019, 30 (Suppl 2):ii48; NCT02737501). | detail... detail... detail... |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Brigatinib | Clinical Study | Actionable | In a retrospective analysis, Alunbrig (brigatinib) demonstrated limited efficacy, resulting in an objective response rate of 17% (3/18) and stable disease in 50% (9/18) of patients with Alecensa (alectinib) refractory, ALK-positive non-small cell lung cancer, with a median progression-free survival of 4.4 months (PMID: 29935304). | 29935304 |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Brigatinib | FDA approved - Has Companion Diagnostic | Actionable | In a Phase II trial (ALTA) that supported FDA approval, Alunbrig (brigatinib) treatment resulted in an overall response rate of 45% (51/112) in the 90mg arm and 54% (59/110) in the 180mg arm, and median progression-free survival of 9.2 and 11.0 months respectively, in ALK-rearranged (fusion) non-small cell lung carcinoma patients who progressed on Xalkori (crizotinib) (PMID: 28475456; NCT02094573). | detail... 28475456 |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Brigatinib | Guideline | Actionable | Alunbrig (brigatinib) is included in guidelines as preferred first-line and as subsequent therapy for patients with advanced or metastatic ALK-rearranged non-small cell lung cancer (NCCN.org). | detail... |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Brigatinib | Guideline | Actionable | Alunbrig (brigatinib) is included in the Pan-Asian Guidelines Adaptation (PAGA) as subsequent therapy for patients who have progressed on second-generation ALK inhibitors (PMID: 30596843; ESMO.org). | 30596843 detail... |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Brigatinib | Phase Ib/II | Actionable | In a Phase I/II trial, Alunbrig (brigatinib) treatment resulted in an objective response rate of 100% (8/8) in ALK inhibitor-naive, ALK-rearranged non-small cell lung cancer (NSCLC) patients, 72% (51/71) in Xalkori (crizotinib) treated ALK-rearranged NSCLC patients, and 83% (5/6) in ALK-rearranged NSCLC patients with CNS metastases (PMID: 27836716; NCT01449461). | 27836716 |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Alectinib | Phase II | Actionable | In a Phase II trial, Alecensa (alectinib) treatment was effective in treating non-small cell lung cancer patients with ALK rearrangement, resulting in a 50% (61/122) objective response rate (ORR) in all patients, a 45% (43/96) ORR in Crizotinib-refractory patients, and an 83% (70/84) CNS disease control rate (PMID: 26598747). | 26598747 |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Alectinib | Clinical Study - Cohort | Actionable | In a retrospective analysis, non-small cell lung cancer patients with brain metastases harboring an ALK rearrangement demonstrated prolonged survival following treatment with the combination of an ALK-targeted tyrosine kinase inhibitor, including Alecensa (alectinib), and radiotherapy (PMID: 26438117). | 26438117 |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Alectinib | Guideline | Actionable | Alecensa (alectinib) is included in guidelines as preferred first-line therapy and as subsequent therapy for patients with ALK-rearranged advanced or metastatic non-small cell lung cancer (NCCN.org). | detail... |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Alectinib | Guideline | Actionable | Alecensa (alectinib) is included in guidelines for patients with metastatic non-small cell lung cancer harboring an ALK rearrangement (PMID: 30285222; ESMO.org). | 30285222 detail... |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Alectinib | Case Reports/Case Series | Actionable | In a clinical case study, Alecensa (alectinib) treatment resulted in disease stability in an HIV-positive pregnant patient with non-small cell lung cancer harboring an ALK translocation, with normal fetal development observed (PMID: 36644155). | 36644155 |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Alectinib | Guideline | Actionable | Alecensa (alectinib) is included in the Pan-Asian Guidelines Adaptation (PAGA) as first-line therapy for non-small cell lung cancer patients with ALK rearrangements, including patients with CNS involvement, and as subsequent therapy for patients that progress on Xalkori (crizotinib) (PMID: 30596843; ESMO.org). | 30596843 detail... |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Alectinib | FDA approved - On Companion Diagnostic | Actionable | In a Phase III trial supporting FDA approval (ALEX), Alecensa (alectinib) treatment resulted in improved rate of progression-free survival compared to Xalkori (crizotinib) (68.4% vs 48.7%, HR=0.47), and median progression-free survival (25.7 vs 10.4 months) in non-small cell lung cancer patients harboring ALK rearrangement (PMID: 28586279; NCT02075840). | 28586279 detail... detail... |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Alectinib | FDA approved - On Companion Diagnostic | Actionable | In a Phase III trial supporting FDA approval (ALINA), adjuvant Alecensa (alectinib) treatment improved 2-year disease-free survival rate (93.8% vs 63.0%, HR 0.24, p<0.001) compared to chemotherapy in patients with resected non-small cell lung cancer harboring ALK rearrangement, and was associated with CNS disease-free survival benefit (HR 0.22) (PMID: 38598794; NCT03456076). | 38598794 detail... detail... |
| ALK rearrange | Advanced Solid Tumor | sensitive | ASP3026 | Phase I | Actionable | In a Phase I trial, ASP3026 treatment resulted in a partial response in 50% (8/16) and stable disease in 44% (7/16) of patients with an advanced solid tumor harboring an ALK rearrangement or ALK F1174L (PMID: 26966027; NCT01284192). | 26966027 |
| ALK rearrange | large cell neuroendocrine carcinoma | predicted - sensitive | Alectinib | Case Reports/Case Series | Actionable | In a clinical case study, Alecensa (alectinib) treatment resulted in a partial response with regression of lesions, including metastatic brain lesions, in a patient with large cell neuroendocrine carcinoma of the lung harboring an ALK rearrangement (PMID: 33352665). | 33352665 |
| ALK rearrange | large cell neuroendocrine carcinoma | predicted - sensitive | Alectinib | Case Reports/Case Series | Actionable | In a clinical case study, Alecensa (alectinib) treatment resulted in a partial response lasting 9 months in a patient with metastatic large-cell neuroendocrine carcinoma of the lung harboring an ALK rearrangement (PMID: 37456922). | 37456922 |
| ALK rearrange | lung non-small cell carcinoma | no benefit | Pembrolizumab | Clinical Study - Cohort | Actionable | In a retrospective analysis, PD-1/PD-L1 inhibitors (Opdivo (nivolumab), Keytruda (pembrolizumab), Durvalumab (MEDI4736), or Tecentriq (atezolizumab)) resulted in lower objective response rate (3.6%, 1/28) in non-small cell lung cancer patients harboring EGFR mutations (22/28) or ALK rearrangement (6/28) compared to EGFR wild-type, ALK negative/unknown patients (23.3%, 7/30) (PMID: 27225694). | 27225694 |
| ALK rearrange | lung non-small cell carcinoma | no benefit | Pembrolizumab | Guideline | Actionable | Immune checkpoint inhibitors including Opdivo (nivolumab), Keytruda (pembrolizumab), Tecentriq (atezolizumab), and Imfinzi (durvalumab) are not indicated for use as subsequent therapy in non-small cell lung cancer patients with ALK rearrangement (NCCN.org). | detail... |
| ALK rearrange | Cancer of Unknown Primary | sensitive | Alectinib | Guideline | Actionable | Alecensa (alectinib) is included in guidelines for patients with cancer of unknown primary harboring ALK rearrangements (PMID: 36563965, PMID: 30285222; ESMO.org). | detail... 30285222 36563965 |
| ALK rearrange | anaplastic large cell lymphoma | not applicable | N/A | Guideline | Prognostic | The presence of ALK rearrangement is associated with a favorable prognosis in patients with anaplastic large cell lymphoma (NCCN.org). | detail... |
| ALK rearrange | anaplastic large cell lymphoma | not applicable | N/A | Guideline | Diagnostic | ALK rearrangement aids in the diagnosis of anaplastic large cell lymphoma (NCCN.org). | detail... |
| ALK rearrange | colon mucinous adenocarcinoma | predicted - sensitive | Crizotinib | Case Reports/Case Series | Actionable | In a Phase Ib trial (PROFILE 1013), Xalkori (crizotinib) therapy resulted in a partial response in a patient with colon mucinous carcinoma harboring ALK rearrangement with a response duration of 103.3 weeks (PMID: 29352732; NCT00939770). | 29352732 |
| ALK rearrange | lung non-small cell carcinoma | no benefit | Nivolumab | Clinical Study - Cohort | Actionable | In a retrospective analysis, PD-1/PD-L1 inhibitors (Opdivo (nivolumab), Keytruda (pembrolizumab), Durvalumab (MEDI4736), or Tecentriq (atezolizumab)) resulted in lower objective response rate (3.6%, 1/28) in non-small cell lung cancer patients harboring EGFR mutations (22/28) or ALK rearrangement (6/28) compared to EGFR wild-type, ALK negative/unknown patients (23.3%, 7/30) (PMID: 27225694). | 27225694 |
| ALK rearrange | lung non-small cell carcinoma | no benefit | Nivolumab | Guideline | Actionable | Immune checkpoint inhibitors including Opdivo (nivolumab), Keytruda (pembrolizumab), Tecentriq (atezolizumab), and Imfinzi (durvalumab) are not indicated for use as subsequent therapy in non-small cell lung cancer patients with ALK rearrangement (NCCN.org). | detail... |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Conteltinib | Phase I | Actionable | In a Phase I trial, Conteltinib (CT-707) demonstrated safety and efficacy in patients with ALK-positive non-small cell lung cancer, resulting in an overall response rate (ORR) of 53.3% (32/60), a disease control rate (DCR) of 80%, and a median progression-free survival of 9.26 months, with an ORR of 61.4% (25/39) and a DCR of 82.1% in ALK inhibitor-naive patients and an ORR of 33.3% (7/21) and a DCR of 76.2% (16/21) in patients previously treated with Xalkori (crizotinib) (PMID: 36424628; NCT02695550). | 36424628 |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Ficonalkib | Phase Ib/II | Actionable | In a Phase I/II trial, Ficonalkib (SY-3505) treatment was well tolerated and resulted in an objective response rate (ORR) of 47.5% (38/80, all partial responses (PR)), disease control rate of 92.5%, median duration of response of 9.23 months, and median progression-free survival of 7.95 months, and an intracranial ORR of 37.5% (12/32, 4 complete responses, 8 PR) and intracranial DCR of 100% (32/32) in Chinese patients with ALK-positive non-small cell lung cancer (PMID: 38295954; NCT05257512). | 38295954 |
| ALK rearrange | renal cell carcinoma | predicted - sensitive | Crizotinib | Case Reports/Case Series | Actionable | In a clinical case study, Xalkori (crizotinib) treatment resulted in a partial response in a patient with metastatic renal cell carcinoma harboring an ALK rearrangement (PMID: 33457258). | 33457258 |
| ALK rearrange | Cancer of Unknown Primary | sensitive | Crizotinib | Guideline | Actionable | Xalkori (crizotinib) is included in guidelines for patients with cancer of unknown primary harboring ALK rearrangements (PMID: 36563965, PMID: 30285222; ESMO.org). | detail... 30285222 36563965 |
| ALK rearrange | Advanced Solid Tumor | sensitive | Belizatinib | Phase Ib/II | Actionable | In a Phase I trial, Belizatinib (TSR-011) treatment resulted in a response in 100% (3/3) of patients with ALK-rearranged advanced solid tumors when administered at higher doses, and stable disease for 7 months or longer in 56% (5/9) of patients at a lower dose (J Clin Oncol 33, 2015 (suppl; abstr 8063)). | detail... |
| ALK rearrange | lung non-small cell carcinoma | no benefit | Gefitinib | Guideline | Actionable | EGFR tyrosine kinase inhibitors including Tarceva (erlotinib), Iressa (gefitinib), Gilotrif (afatinib), and Tagrisso (osimertinib) are not indicated for use as subsequent therapy in ALK rearranged non-small cell lung cancer patients who relapsed on Alecensa (alectinib), Xalkori (crizotinib), or Zykadia (ceritinib) (NCCN.org). | detail... |
| ALK rearrange | lung adenocarcinoma | predicted - sensitive | Bevacizumab + Lorlatinib | Case Reports/Case Series | Actionable | In a clinical case study, a lung adenocarcinoma patient with brain metastasis harboring an ALK rearrangement, who had progressed on single agent Lorbrena (lorlatinib) treatment, demonstrated a partial response when treated with a combination of Lorbrena (lorlatinib) and Avastin (bevacizumab), with a 68% decrease in tumor size in the brain and a total duration of disease control for 9.1 months (PMID: 33283131). | 33283131 |
| ALK rearrange | lung adenocarcinoma | predicted - sensitive | Alectinib | Case Reports/Case Series | Actionable | In a clinical case study, Alecensa (alectinib) treatment resulted in a partial response in a pregnant patient with ALK-rearranged metastatic lung adenocarcinoma, with normal fetal development and infant development for at least the first 20 months post birth (PMID: 33795207). | 33795207 |
| ALK rearrange | malignant pleural mesothelioma | no benefit | Conteltinib | Case Reports/Case Series | Actionable | In a Phase I trial, Conteltinib (CT-707) treatment resulted in disease progression after 1 cycle in a patient with ALK-rearranged malignant pleural mesothelioma (PMID: 32181989). | 32181989 |
| ALK rearrange | lung non-small cell carcinoma | no benefit | Afatinib | Guideline | Actionable | EGFR tyrosine kinase inhibitors including Tarceva (erlotinib), Iressa (gefitinib), Gilotrif (afatinib), and Tagrisso (osimertinib) are not indicated for use as subsequent therapy in ALK rearranged non-small cell lung cancer patients who relapsed on Alecensa (alectinib), Xalkori (crizotinib), or Zykadia (ceritinib) (NCCN.org). | detail... |
| ALK rearrange | lung non-squamous non-small cell carcinoma | sensitive | Ceritinib | Phase III | Actionable | In a Phase III trial, first-line treatment with Zykadia (ceritinib) resulted in an improved median progression-free survival of 16.6 months, compared to 8.1 months with chemotherapy, in patients with ALK-rearranged non-squamous non-small cell lung cancer (PMID: 28126333; NCT01828099). | 28126333 |
| ALK rearrange | lung adenocarcinoma | predicted - sensitive | Conteltinib | Phase I | Actionable | In a Phase I trial, Conteltinib (CT-707) demonstrated safety and preliminary efficacy, resulting in an overall response rate of 77% (10/13, 1 complete response, 9 partial responses) and a disease control rate of 85% (11/13) in patients with ALK-rearranged lung adenocarcinoma (n=12) or malignant pleural mesothelioma (n=1), median progression-free survival was 13 months in patients with lung adenocarcinoma (PMID: 32181989). | 32181989 |
| ALK rearrange | Advanced Solid Tumor | predicted - sensitive | Entrectinib | Clinical Study | Actionable | In a combined analysis of 2 Phase I trials (ALKA-372-001, STARTRK-1), Rozlytrek (entrectinib) treatment resulted in an objective response rate of 57% (4/7) in patients with ALK-rearranged advanced solid tumors that were treatment-naive, but no response (0/19) in patients who received prior Alk inhibitor treatments (PMID: 28183697; NCT02097810). | 28183697 |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Ensartinib | Clinical Study - Cohort | Actionable | In a retrospective analysis, non-small cell lung cancer patients with brain metastases harboring an ALK rearrangement demonstrated prolonged survival following treatment with the combination of an ALK-targeted tyrosine kinase inhibitor, including Ensartinib (X-396), and radiotherapy (PMID: 26438117). | 26438117 |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Ensartinib | Phase III | Actionable | In a Phase III trial, Ensartinib (X-396) treatment significantly improved progression-free survival in patients with ALK-positive non-small cell lung cancer (25.8 vs 12.7 mo, HR 0.51, p<0.001) compared to Xalkori (crizotinib), and resulted in an intracranial response rate of 63.6% (7 of 11) in patients with target brain metastases at baselinewith compared to 21.1% (4 of 19) with Xalkori (crizotinib) (PMID: 34473194; NCT02767804). | 34473194 |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Ensartinib | Phase Ib/II | Actionable | In a Phase I/II trial, Ensartinib (X-396) treatment resulted in partial response in 60% (36/60) and stable disease in 21.7 % (13/60) of patients with ALK-positive non-small cell lung cancer, with a median progression-free survival of 9.2 months, and a response rate of 80% (12/15) in crizotinib-naïve patients and 69% (20/29) in patients with prior crizotinib treatment (PMID: 29563138; NCT01625234). | 29563138 |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Ensartinib | Guideline | Actionable | Ensartinib (X-396) is included in guidelines for patients with metastatic non-small cell lung cancer harboring an ALK rearrangement (PMID: 30285222, Version Update 15 Sept 2020; ESMO.org). | detail... 30285222 |
| ALK rearrange | anaplastic large cell lymphoma | sensitive | Alectinib | Guideline | Actionable | Alecensa (alectinib) is included in guidelines as second-line and subsequent therapy for patients with anaplastic large cell lymphoma harboring ALK rearrangements (NCCN.org). | detail... |
| ALK rearrange | lung non-small cell carcinoma | no benefit | Durvalumab | Guideline | Actionable | Immune checkpoint inhibitors including Opdivo (nivolumab), Keytruda (pembrolizumab), Tecentriq (atezolizumab), and Imfinzi (durvalumab) are not indicated for use as subsequent therapy in non-small cell lung cancer patients with ALK rearrangement (NCCN.org). | detail... |
| ALK rearrange | lung non-small cell carcinoma | no benefit | Durvalumab | Clinical Study - Cohort | Actionable | In a retrospective analysis, PD-1/PD-L1 inhibitors (Opdivo (nivolumab), Keytruda (pembrolizumab), Imfinzi (durvalumab), or Tecentriq (atezolizumab)) resulted in lower objective response rate (3.6%, 1/28) in non-small cell lung cancer patients harboring EGFR mutations (22/28) or ALK rearrangement (6/28) compared to EGFR wild-type, ALK negative/unknown patients (23.3%, 7/30) (PMID: 27225694). | 27225694 |
| ALK rearrange | inflammatory myofibroblastic tumor | sensitive | Brigatinib | Guideline | Actionable | Alunbrig (brigatinib) is included in guidelines as first-line therapy for patients with advanced, recurrent, metastatic, or inoperable inflammatory myofibroblastic tumor harboring ALK translocations (NCCN.org). | detail... |
| ALK rearrange | anaplastic large cell lymphoma | sensitive | Brigatinib | Guideline | Actionable | Alunbrig (brigatinib) is included in guidelines as initial, second-line, and subsequent therapy for patients with anaplastic large cell lymphoma harboring ALK rearrangements (NCCN.org). | detail... |
| ALK rearrange | Cancer of Unknown Primary | sensitive | Brigatinib | Guideline | Actionable | Alunbrig (brigatinib) is included in guidelines for patients with cancer of unknown primary harboring ALK rearrangements (PMID: 36563965, PMID: 30285222; ESMO.org). | 30285222 detail... 36563965 |
| ALK rearrange | anaplastic large cell lymphoma | sensitive | Crizotinib | FDA approved | Actionable | In a Phase I/II trial that supported FDA approval, Xalkori (crizotinib) treatment resulted in an objective response rate (ORR) of 83% (5/6, all complete responses (CR)) at the 165 mg dose, and an ORR of 90% (18/20, 16 CR) at the 280 mg dose, in pediatric patients 1 years of age or older and young adults with relapsed or refractory ALK-positive anaplastic large cell lymphoma (PMID: 28787259; NCT00939770). | 28787259 detail... |
| ALK rearrange | anaplastic large cell lymphoma | sensitive | Crizotinib | Guideline | Actionable | Xalkori (crizotinib) is included in guidelines as second-line and subsequent therapy for patients with anaplastic large cell lymphoma harboring ALK rearrangements (NCCN.org). | detail... |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Iruplinalkib | Phase I | Actionable | In a Phase I trial, Iruplinalkib (WX-0593) demonstrated safety and resulted in an objective response rate (ORR) of 56.6% (56/99; all partial responses) and a disease control rate (DCR) of 83.8% (83/99), and median duration of response and median progression-free survival were not reached in non-small cell lung cancer patients with an ALK or ROS1-rearrangement, with an ORR of 58.2% (53/91; all partial responses) and DCR of 85.7% (78/91) in patients with an ALK rearrangement (PMID: 35087031; NCT03389815). | 35087031 |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Iruplinalkib | Phase II | Actionable | In a Phase II trial (INTELLECT), Iruplinalkib (WX-0593) treatment resulted in an IRC-assessed objective response rate (ORR) of 69.9% (102/146), investigator-assessed ORR of 63.0%, disease control rate of 94.5%, and median progression-free survival of 14.5 months in patients with ALK-positive, Crizotinib-resistant non-small cell lung cancer, and an intracranial ORR of 46% (41/90) and 64% (27/42) for patients with CNS metastases or measurable intracranial lesions, respectively (PMID: 36829154; NCT04641754). | 36829154 |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Iruplinalkib | Phase III | Actionable | In a Phase III trial (INSPIRE), Iruplinalkib (WX-0593) treatment in ALK-positive non-small cell lung cancer patients resulted in a significantly improved median progression free survival (mPFS) of 27.7 months, improved objective response rate (ORR) of 93.0% (133/143), and intracranial ORR of 90.9% (10/11) compared to a mPFS of 14.6 months (HR=0.34, p<0.0001), ORR of 89.3% (133/149), and intracranial ORR of 60.0% (9/15) with Xalkori (crizotinib) treatment (PMID: 38280448; NCT04632758). | 38280448 |
| ALK rearrange | lung non-small cell carcinoma | no benefit | Ipilimumab + Nivolumab | Guideline | Actionable | Immune checkpoint inhibitors including Keytruda (pembrolizumab), Tecentriq (atezolizumab), and the combination of Opdivo (nivolumab) and Yervoy (ipilimumab) are not indicated for use as initial systemic therapy in non-small cell lung cancer patients harboring oncogenes, including ALK rearrangement (NCCN.org). | detail... |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Lorlatinib | Phase II | Actionable | In a Phase II trial, Lorbrena (lorlatinib) treatment resulted in an intracranial disease control rate of 95% (21/22), intracranial objective response rate of 59% (13/22; 6 complete responses, 7 partial responses), a median intracranial progression-free survival (PFS) rate of 24.6 months, and a 12-month PFS rate of 79% in patients with ALK-rearranged non-small cell lung cancer, who previously demonstrated central nervous system progression on second-generation ALK inhibitors (PMID: 35584349; NCT02927340). | 35584349 |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Lorlatinib | FDA approved - On Companion Diagnostic | Actionable | In a Phase III trial (Study B7461006) that supported FDA approval, first-line Lorbrena (lorlatinib) treatment resulted in a significantly improved 12-mo progression-free survival rate (78% vs 39%, HR 0.28, p<0.0010) and a response rate of 76% (113/149) vs 58% (85/147) compared to Xalkori (crizotinib) in patients with advanced ALK-positive non-small cell lung cancer, and led to an intracranial response rate of 71% (12/14) vs 23% (3/13) in patients with measurable CNS metastases (PMID: 33207094; NCT03052608). | 33207094 detail... detail... |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Lorlatinib | Guideline | Actionable | Lorbrena (lorlatinib) is included in guidelines for patients with metastatic non-small cell lung cancer harboring an ALK rearrangement who have progressed on an ALK tyrosine kinase inhibitor (PMID: 30285222; ESMO.org). | 30285222 detail... |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Lorlatinib | Phase I | Actionable | In a Phase I trial, Lorbrena (lorlatinib) treatment resulted in an objective response in 46% (19/41) of patients with non-small cell lung carcinoma harboring an ALK rearrangement (PMID: 29074098; NCT03052608). | 29074098 |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Lorlatinib | FDA approved - On Companion Diagnostic | Actionable | In a Phase II trial that supported FDA approval, Lorbrena (lorlatinib) treatment resulted in an objective response (OR) rate of 47% (93/198; 4 CR, 89 PR) and a median time to overall first tumor response of 1.4 months, and an objective intracranial response rate of 63% (51/81) and median time to first intracranial response of 1.4 months in ALK-positive (rearrangement or fusion) non-small cell lung cancer patients who had received at least one prior ALK inhibitor therapy (PMID: 30413378; NCT01970865). | detail... detail... 30413378 |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Lorlatinib | Guideline | Actionable | Lorbrena (lorlatinib) is included in guidelines as preferred first-line therapy and as subsequent therapy for patients with advanced or metastatic ALK-rearranged non-small cell lung cancer (NCCN.org). | detail... |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Lorlatinib | Phase III | Actionable | In a Phase III trial (CROWN), Lorbrena (lorlatinib) treatment (n=149) demonstrated superior efficacy compared to Xalkori (crizotinib) (n=147) at 5-year follow-up in ALK-positive (rearrangement or fusion) non-small cell lung cancer patients, with improved median progression-free survival (PFS, not reached vs 9.1 months, HR 0.19), 5-year PFS rate (60% vs 8%), and median time to intracranial progression (not reached vs 16.4 months) (PMID: 38819031; NCT03052608). | 38819031 |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Lorlatinib | Guideline | Actionable | Lorbrena (lorlatinib) is included in the Pan-Asian Guidelines Adaptation (PAGA) as subsequent therapy for patients who have progressed on second-generation ALK inhibitors (PMID: 30596843; ESMO.org). | 30596843 detail... |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Lorlatinib | Phase Ib/II | Actionable | In a Phase I/II trial, Lorbrena (lorlatinib) treatment resulted in an objective response rate (ORR) of 82.4% (14/17, all partial responses (PR)) and 63.6% (21/33, all PR) in Asian and non-Asian patients with ALK-positive non-small cell lung cancer who had prior Xalkori (crizotinib) treatment and an ORR of 47.2% (25/53, 2 complete responses, 23 PR) and 30.1% (22/73, all PR) in patients previously treated with any second-generation ALK inhibitor (PMID: 35660971; NCT01970865). | 35660971 |
| ALK rearrange | lymphoma | predicted - sensitive | Crizotinib | Phase I | Actionable | In a Phase Ib trial (PROFILE 1013), Xalkori (crizotinib) treatment resulted in an objective response rate of 52.9% (9/17, 8 complete responses, 1 partial response) and stable disease in 17.6% (3/17) of patients with advanced ALK-positive lymphomas, with a median duration of response of 135.9 weeks in (PMID: 29352732; NCT00939770). | 29352732 |
| ALK rearrange | lung non-small cell carcinoma | predicted - sensitive | Foritinib | Phase Ib/II | Actionable | In a Phase I/II trial, Foritinib was well tolerated in ALK-positive non-small cell lung cancer patients, and resulted in a disease control rate (DCR) of 100% and median progression-free survival (PFS) of 33.1 mo in ALK inhibitor (ALKi)-naive and 22.1 mo in ALKi-pretreated patients in Phase I, and a DCR of 98.1% and 88.5%, and objective response rate of 92.3% and 65.4%, in ALKi-naive or crizotinib-pretreated patients, respectively, in Phase II (J Clin Oncol 40, 2022 (suppl 16; abs 9076); NCT04237805). | detail... |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Ceritinib + Crizotinib | Clinical Study - Cohort | Actionable | In a retrospective analysis of patients with ALK-rearrangement positive non-small cell lung cancer, the combined median progression-free survival for sequential treatment with Xalkori (crizotinib) and Zykadia (ceritinib) without intervening treatments was 17.0 months, and overall survival was 49.4 months (PMID: 25724526). | 25724526 |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Ceritinib | Guideline | Actionable | Zykadia (ceritinib) is included in the Pan-Asian Guidelines Adaptation (PAGA) as first-line therapy for non-small cell lung cancer patients with ALK rearrangements, including patients with CNS involvement, and as subsequent therapy for patients that progress on Xalkori (crizotinib) (PMID: 30596843; ESMO.org). | detail... 30596843 |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Ceritinib | Phase II | Actionable | In a Phase II trial (ASCEND-2), non-small cell lung cancer patients with brain metastases harboring an ALK rearrangement and previously treated with Xalkori (crizotinib) and chemotherapy demonstrated an overall response rate of 38.6% (54/140), a disease control rate of 77.1%, a median time to response of 1.8 months, a median duration of response of 9.7 months, and a median progression-free survival of 5.7 months when treated with Zykadia (ceritinib) (PMID: 27432917; NCT01685060). | 27432917 |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Ceritinib | Guideline | Actionable | Zykadia (ceritinib) is included in guidelines as first-line and as subsequent therapy for patients with advanced or metastatic ALK-rearranged non-small cell lung cancer (NCCN.org). | detail... |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Ceritinib | Clinical Study - Cohort | Actionable | In a retrospective analysis, non-small cell lung cancer patients with brain metastases harboring an ALK rearrangement demonstrated a median overall survival of 49.5 months following treatment with the combination of an ALK-targeted tyrosine kinase inhibitor, including Zykadia (ceritinib), and radiotherapy (PMID: 26438117). | 26438117 |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Ceritinib | FDA approved - On Companion Diagnostic | Actionable | In a Phase I trial that supported FDA approval, Zykadia (ceritinib) resulted in a blinded independent review committee (BIRC)-assessed objective response rate of 44% (72/163) and a duration of response of 7.1 months in ALK-rearranged non-small cell lung cancer patients (PMID: 25754348; NCT01283516). | 25754348 detail... detail... |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Ceritinib | Phase II | Actionable | In a Phase II trial (ASCEND-7), Zykadia (ceritinib) demonstrated efficacy in ALK-positive non-small cell lung cancer patients with active brain metastasis, resulting in whole-body overall response rate (ORR) of 35.7% (15/42), 30.0% (12/40), 50.0% (6/12), and 59.1% (26/44) in those who received prior radiation/ALK inhibitor (ALKi), ALKi only, radiation only, no prior radiation/ALKi, respectively, and whole-body ORR of 16.7% (3/18) in patients with leptomeningeal carcinomatosis (PMID: 35091443; NCT02336451). | 35091443 |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Ceritinib | Guideline | Actionable | Zykadia (ceritinib) is included in guidelines for patients with metastatic non-small cell lung cancer harboring an ALK rearrangement (PMID: 30285222; ESMO.org). | detail... 30285222 |
| ALK rearrange | lung non-small cell carcinoma | predicted - sensitive | Ceritinib + Ribociclib | Phase Ib/II | Actionable | In a Phase I/II trial, Zykadia (ceritinib) and Kisqali (ribociclib) combination therapy demonstrated a manageable safety profile and resulted in an overall response rate of 37.0% (10/27; 1 complete response and 9 partial responses) with a median progression-free survival of 21.5 months in patients with advanced ALK-rearranged non-small cell lung cancer (PMID: 35298959). | 35298959 |
| ALK rearrange | epithelioid inflammatory myofibroblastic sarcoma | predicted - sensitive | Alectinib | Case Reports/Case Series | Actionable | In a clinical case study, Alecensa (alectinib) treatment resulted in a complete response lasting 44.2 months in a pediatric patient with an ALK-rearranged epithelioid inflammatory myofibroblastic tumor (PMID: 34036223). | 34036223 |
| ALK rearrange | lung non-small cell carcinoma | no benefit | Osimertinib | Guideline | Actionable | EGFR tyrosine kinase inhibitors including Tarceva (erlotinib), Iressa (gefitinib), Gilotrif (afatinib), and Tagrisso (osimertinib) are not indicated for use as subsequent therapy in ALK rearranged non-small cell lung cancer patients who relapsed on Alecensa (alectinib), Xalkori (crizotinib), or Zykadia (ceritinib) (NCCN.org). | detail... |
| ALK rearrange | anaplastic large cell lymphoma | sensitive | Ceritinib | Phase I | Actionable | In a Phase I trial, Zykadia (ceritinib) treatment was well tolerated and resulted in an overall response rate of 75% (6/8; 2 complete responses, 4 partial responses) and a disease control rate of 88% (7/8) in pediatric patients with anaplastic large cell lymphoma harboring ALK rearrangement, with median progression-free survival not reached (PMID: 34780709; NCT01742286). | 34780709 |
| ALK rearrange | anaplastic large cell lymphoma | sensitive | Ceritinib | Guideline | Actionable | Zykadia (ceritinib) is included in guidelines as initial, second-line, and subsequent therapy for patients with anaplastic large cell lymphoma harboring ALK rearrangements (NCCN.org). | detail... |
| ALK rearrange | lung small cell carcinoma | predicted - sensitive | Alectinib + Irinotecan | Case Reports/Case Series | Actionable | In a clinical case study, treatment with the combination of Alecensa (alectinib) and Camptosar (irinotecan) resulted in a partial response with progression-free survival lasting longer than 6 months in a small cell lung carcinoma patient harboring an ALK rearrangement (PMID: 34729013). | 34729013 |
| ALK rearrange | Advanced Solid Tumor | predicted - sensitive | TQ-B3101 | Phase I | Actionable | In a Phase I trial, TQ-B3101 treatment was well tolerated and resulted in an objective response rate (ORR) of 62.5% (15/24) in patients with ALK-positive, ROS1-positive, or MET-amplified advanced solid tumors, with an ORR of 62.5% (5/8) in patients with brain metastases (J Clin Oncol 38, 2020 (suppl 15; abstr e21705); NCT03019276). | detail... |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Crizotinib | Phase III | Actionable | In a Phase III trial (PROFILE 1014), Xalkori (crizotinib) treatment resulted in improved progression-free survival (PFS) (PFS=10.9 months, n=172) relative to chemotherapy (PFS=7.0 months, n=171) in NSCLC patients with ALK rearrangements, including patients with and without brain metastases at baseline, and improved intracranial disease rate in patients with brain metastases at baseline (PMID: 27022118; NCT01154140). | 27022118 |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Crizotinib | Phase III | Actionable | In a Phase III trial, Xalkori (crizotinib) treatment resulted in improved objective response (87.5%, 90/103 vs 45.6%, 47/103) and median progression free survival (11.1 vs 6.8 mo) compared to pemetrexed, cisplatin and carboplatinin combination treatment in treatment-naive ALK positive advanced non-small cell lung carcinoma patients (J Clin Oncol 34, 2016 (suppl; abstr 9058); NCT01639001). | detail... |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Crizotinib | Guideline | Actionable | Xalkori (crizotinib) is included in guidelines as first-line therapy for ALK rearranged non-small cell lung cancer (NCCN.org). | detail... |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Crizotinib | FDA approved - On Companion Diagnostic | Actionable | In a Phase III trial (PROFILE 1014) that supported FDA approval, Xalkori (crizotinib) treatment resulted in improved progression-free survival (10.9 vs 7.0 months, HR=0.45, p<0.001) and objective response rate (74% vs 45%) relative to chemotherapy in NSCLC patients with ALK rearrangements (PMID: 25470694; NCT01154140). | detail... 25470694 detail... |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Crizotinib | Guideline | Actionable | Xalkori (crizotinib) is included in the Pan-Asian Guidelines Adaptation (PAGA) as first-line therapy for non-small cell lung cancer patients with ALK rearrangements (PMID: 30596843; ESMO.org). | detail... 30596843 |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Crizotinib | Clinical Study | Actionable | In a clinical study, Xalkori (crizotinib) treatment resulted in an objective response rate of 59.3% (48/81, 8 complete responses), clinical benefit rate of 86.4% (70/81), median duration of response of 13.5 months, median progression-free survival of 15.8 months, and median overall survival of 46.5 months in patients with non-small cell lung cancer harboring an ALK rearrangement (PMID: 36162227; NCT02679170). | 36162227 |
| ALK rearrange | lung non-small cell carcinoma | sensitive | Crizotinib | Guideline | Actionable | Xalkori (crizotinib) is included in guidelines as first-line therapy for patients with metastatic non-small cell lung cancer harboring an ALK rearrangement, or as a next-line therapy in patients with ALK-rearranged non-small cell lung cancer who have not received prior Xalkori (crizotinib) (PMID: 30285222; ESMO.org). | 30285222 detail... |
| ALK rearrange | inflammatory myofibroblastic tumor | sensitive | Alectinib | Guideline | Actionable | Alecensa (alectinib) is included in guidelines as first-line therapy for patients with advanced, recurrent, metastatic, or inoperable inflammatory myofibroblastic tumor harboring ALK translocations (NCCN.org). | detail... |
| ALK rearrange | lung non-small cell carcinoma | no benefit | Atezolizumab | Guideline | Actionable | Immune checkpoint inhibitors including Opdivo (nivolumab), Keytruda (pembrolizumab), Tecentriq (atezolizumab), and Imfinzi (durvalumab) are not indicated for use as subsequent therapy in non-small cell lung cancer patients with ALK rearrangement (NCCN.org). | detail... |
| ALK rearrange | lung non-small cell carcinoma | no benefit | Atezolizumab | Clinical Study - Cohort | Actionable | In a retrospective analysis, PD-1/PD-L1 inhibitors (Opdivo (nivolumab), Keytruda (pembrolizumab), Durvalumab (MEDI4736), or Tecentriq (atezolizumab)) resulted in lower objective response rate (3.6%, 1/28) in non-small cell lung cancer patients harboring EGFR mutations (22/28) or ALK rearrangement (6/28) compared to EGFR wild-type, ALK negative/unknown patients (23.3%, 7/30) (PMID: 27225694). | 27225694 |
| ALK mutant | lung non-small cell carcinoma | no benefit | Crizotinib + Onalespib | Phase II | Actionable | In a Phase II trial, Onalespib (AT13387) and Xalkori (crizotinib) combination treatment did not significantly improve median progression free survival (269 vs 266 days) or objective response rate (55.4%, 38/68 vs 45.3%, 31/68) compared to Xalkori (crizotinib) single treatment in patients with non-small cell lung carcinoma harboring either an ALK mutation or ALK rearrangement (J Clin Oncol 34, 2016 (suppl; abstr 9059); NCT01712217). | detail... |
| ALK mutant | lung non-small cell carcinoma | no benefit | Belizatinib | Phase I | Actionable | In a Phase I trial, treatment with Belizatinib (TSR-011) in ALK inhibitor-naive non-small cell lung cancer patients (n=14) harboring either an ALK mutation, ALK amplification, or an ALK rearrangement resulted in a partial response in 6 patients and stable disease in 8 patients, however, it was determined that the drug resulted in limited efficacy and development of the drug was discontinued (PMID: 31217479; NCT02048488). | 31217479 |
| ALK act mut | neuroblastoma | predicted - sensitive | S63845 + Trametinib | Preclinical - Cell culture | Actionable | In a preclinical study, the addition of Mekinist (trametinib) sensitized a neuroblastoma cell line harboring an ALK activating mutation to S63845 (MIK655), resulting in reduced cell viability in culture (PMID: 36895472). | 36895472 |
| ALK act mut | neuroblastoma | sensitive | Lorlatinib | Phase I | Actionable | In a Phase I trial, Lorbrena (lorlatinib) treatment was well tolerated and resulted in a modified response rate of 30% (7/23) in children and 67% (10/15) in adults with neuroblastoma harboring an ALK activating mutation, including ALK F1174C, F1174L, R1275Q, or R1275L, F1245Y, F1245L, D1276_R1279delinsE, or amplification (PMID: 37012551; NCT03107988). | 37012551 |
| ALK act mut | neuroblastoma | predicted - sensitive | NVL-655 | Preclinical - Cell culture | Actionable | In a preclinical study, NUV-655 inhibited proliferation of neuroblastoma cell lines harboring activating mutations in ALK in culture (Cancer Res (2022) 82 (12_Supplement): 3337). | detail... |
| ALK act mut | neuroblastoma | sensitive | Cyclophosphamide + Lorlatinib + Topotecan | Phase I | Actionable | In a Phase I trial, the combination of Lorbrena (lorlatinib), Topotecan, and Cytoxan (cyclophosphamide) treatment was well tolerated and resulted in a modified response rate of 63% (5/8) in pediatric patients with neuroblastoma harboring an ALK activating mutation, including ALK F1174C, F1174L, R1275Q, or R1275L (PMID: 37012551; NCT03107988). | 37012551 |
| ALK act mut | neuroblastoma | predicted - sensitive | Navitoclax + Trametinib | Preclinical - Cell culture | Actionable | In a preclinical study, the addition of Mekinist (trametinib) sensitized neuroblastoma cell lines harboring ALK activating mutations to Navitoclax (ABT-263), resulting in reduced cell viability in culture (PMID: 36895472). | 36895472 |
| ALK act mut | neuroblastoma | predicted - sensitive | Trametinib + Venetoclax | Preclinical - Cell culture | Actionable | In a preclinical study, the addition of Mekinist (trametinib) sensitized a neuroblastoma cell line harboring an ALK activating mutation to Venclexta (venetoclax), resulting in reduced cell viability in culture (PMID: 36895472). | 36895472 |