- |||||||||| Zykadia (ceritinib) / Novartis
Trial completion date, Metastases: Ceritinib Plus Docetaxel in ALK-Negative, EGFR WT Advanced NSCLC (clinicaltrials.gov) - Sep 19, 2024
P1, N=21, Active, not recruiting,
A series of rigid ALK PROTACs were developed through conjugation of Ceritinib and thalidomide, orally bioavailable PROTAC 4B (F Trial completion date: Apr 2025 --> Apr 2026
- |||||||||| Lorbrena (lorlatinib) / Pfizer, Xalkori (crizotinib) / Pfizer, Vizimpro (dacomitinib) / Pfizer
Trial completion, Enrollment change, Trial completion date, Trial primary completion date, Metastases: DELINOR: A Study to Learn About the Effectiveness of Cancer Medicines in Patients With Metastatic Non-small Cell Lung Cancer in Norway. (clinicaltrials.gov) - Sep 4, 2024
P=N/A, N=1, Completed,
Trial completion date: Apr 2025 --> Apr 2026 Recruiting --> Completed | N=20605 --> 1 | Trial completion date: Feb 2025 --> Jan 2024 | Trial primary completion date: Feb 2025 --> Jan 2024
- |||||||||| Zykadia (ceritinib) / Novartis
Journal: In-cell bioluminescence resonance energy transfer (BRET)-based assay uncovers ceritinib and CA-074 as SARS-CoV-2 papain-like protease inhibitors. (Pubmed Central) - Aug 20, 2024
Using this assay, three protease inhibitors were identified as novel PLpro inhibitors that are structurally disparate from those previously known. Subsequent enzymatic assays and ligand-protein interaction analysis based on molecular docking revealed that ceritinib directly inhibited PLpro, showing high geometric complementarity with the substrate-binding pocket in PLpro, whereas CA-074 methyl ester underwent intracellular hydrolysis, exposing a free carboxyhydroxyl group essential for hydrogen bonding with G266 in the BL2 groove, resulting in PLpro inhibition.
- |||||||||| Lorbrena (lorlatinib) / Pfizer
A Patient-Centric, Phase II Trial of First-Line Lorlatinib&alk TKIs in China Advanced ALK+ Non-Small Cell Lung Cancer (Exhibit Hall) - Jul 24, 2024 - Abstract #IASLCWCLC2024IASLC_WCLC_2211;
The RO cohort is designed to serve as comparison cohort, which will enroll 63 treatment-naive subjects who may receive crizotinib, ceritinib, alectinib, brigatinib, ensartinib, lorlatinib, etc. Real-world efficacy and safety data of ALK TKIs were collected in the same cross-section. The primary endpoint is real-world progression-free survival (rwPFS) of ALK TKIs in the first-line treatment of advanced NSCLC patients with ALK fusion.
- |||||||||| OBX02-011 / Oncobix
OBX02-011, a Novel Oral ALK and EGFR Dual-target Tyrosine Kinase Inhibitor for the Treatment of Advanced NSCLC Patients (Exhibit Hall) - Jul 24, 2024 - Abstract #IASLCWCLC2024IASLC_WCLC_2194;
In addition, OBX02-011 demonstrated superior inhibition compared to lorlatinib in ALK_C1156Y, G1202R, and L1196M mutations associated with clinical resistance to the first generation ALK inhibitor crizotinib and/or the second generation ALK inhibitors alectinib, brigatinib, and ceritinib...OBX02-011 also demonstrated tumor regression in the osimertinib-resistant lung cancer patient-derived xenograft model with EGFR_exon 19 deletion/T790M/C797S...In vitro cell-based assay results showed that OBX02-011 does not inhibit NTRK2 (TRKB), which causes neurological toxicity, and there were also no significant findings for OBX02-011 in the CNS safety pharmacology study. Based on these studies, a first-in-human study will be conducted in 2024 to address the current resistance mechanisms in ALK-positive or EGFR-positive NSCLC patients and prolong progression free survival.
- |||||||||| Characterizing the Severity and Timing of Real-World ALK-Inhibitor Associated Weight Gain in Non-Small Cell Lung Cancer (Exhibit Hall) - Jul 24, 2024 - Abstract #IASLCWCLC2024IASLC_WCLC_2170;
Future investigation of optimal prevention and management of weight gain is encouraged. Table 1: Real World Weight Gain Characteristics on ALK-TKIs Crizotinib Brigatinib Alectinib Lorlatinib p-value Mean Max Weight Gain (% baseline) [95% CI] +4.2% [1.9-6.7] +4.5% [2.3-6.6] +6.4% [4.4-8.5] +13.3% [9.3-17.4] <0.001 Mean Time to Max Weight Gain (mo) [95% CI] 20.0mo [12.4-27.6] 24.6mo [14.0-35.2] 16.0mo [11.8-20.1] 22.2mo [13.7-30.8] 0.24 Mean Max Weight Gain by 6 mo (% baseline) [95% CI] -1.4% [-4.0-1.2] +0.9% [-1.2-3.0] +3.2% [1.3-5.1] +5.8% [2.9-8.7] 0.02 % Grade 2-3 Weight Gain [% Grade 3] 11.8% [0%] 13.0% [0%] 30.2% [3.9%] 61.3% [29.0%] <0.001
- |||||||||| Lorbrena (lorlatinib) / Pfizer
Patterns of Progression with Lorlatinib and Insights into Subsequent Anticancer Therapy Efficacy in Advanced ALK+ NSCLC (20D) - Jul 24, 2024 - Abstract #IASLCWCLC2024IASLC_WCLC_978;
P3
Best Overall Response and Objective Response Rate on First Subsequent Anticancer Therapy Study treatment Lorlatinib Crizotinib First Subsequent Therapy Any ALK TKI (n=23) a Any non-ALK TKI (n=15) b Overall (n=38) Any ALK TKI (n=101) a Any non-ALK TKI (n=8) b Overall (n=109) Objective response rate (95% CI), % c 26.1 (10.2-48.4) 20.0 (4.3-48.1) 23.7 (11.4-40.2) 17.8 (10.9-26.7) 12.5 (0.3-52.7) 17.4 (10.8-25.9) Best overall response, n (%) Complete response 2 (9) 1 (7) 3 (8) 1 (1) 0 1 (1) Partial response 4 (17) 2 (13) 6 (16) 17 (17) 1 (13) 18 (17) Stable disease 1 (4) 3 (20) 4 (11) 23 (23) 0 23 (21) Progressive disease 6 (26) 3 (20) 9 (24) 10 (10) 2 (25) 12 (11) Unknown 3 (13) 5 (33) 8 (21) 9 (9) 4 (50) 13 (12) Not reported, therapy ongoing 7 (30) 1 (7) 8 (21) 41 (41) 1 (13) 42 (39) a Includes alectinib, brigatinib, ceritinib, crizotinib, and lorlatinib. b Includes chemotherapy
- |||||||||| Zykadia (ceritinib) / Novartis
Trial completion date, Trial primary completion date, Combination therapy: Study of Safety and Efficacy of Ceritinib in Combination With Nivolumab in Patients With ALK-positive Non-small Cell Lung Cancer (clinicaltrials.gov) - Jun 19, 2024
P1, N=57, Active, not recruiting,
Patient-sourced drug sensitivity testing of lung cancer-like organs selects drug-sensitive medications based on NGS results and provides a reference for subsequent drug therapy for patients after drug resistance, particularly those who remain ALK rearrangement-positive at baseline. Trial completion date: Sep 2024 --> Apr 2025 | Trial primary completion date: Sep 2024 --> Apr 2025
- |||||||||| Zykadia (ceritinib) / Novartis
Journal: The synthesis and evaluation of novel ALK inhibitors containing the sulfoxide structure. (Pubmed Central) - Jun 3, 2024
With ceritinib as the lead, a series of novel compounds containing the sulfoxide structure were synthesized and evaluated as anaplastic lymphoma kinase inhibitors...Using 18d as a representative, which exhibited the best in vivo results, we carried out mechanistic studies such as anti-colony formation, induced tumor cell apoptosis, ALK kinase protein phosphorylation in H2228 tumor cells, and molecular docking. All these results indicate that compound 18d is a good anti-tumor lead compound and worthy of further study.
- |||||||||| Review, Journal: Comprehensive review of ROS1 tyrosine kinase inhibitors (TKIs)-classified by structural designs and mutation spectrum [solvent front mutation (G2032R) and central ?-sheet 6 (C?6) mutation (L2086F)]. (Pubmed Central) - May 8, 2024
Despite ROS1 fusion-positive NSCLC accounting for approximately 1% to 2% of NSCLC, there is a long list of ROS1 tyrosine kinase inhibitors (TKIs) being developed in addition to three approved ROS1 TKIs, crizotinib, entrectinib and repotrectinib...Additionally, the less known central ?-sheet 6 (C?6) mutation ROS1 L2086F confer resistances to next-generation ROS1 TKIs (taletrectinib, lorlatinib, potentially NVL-520) that can be overcome by cabozantinib as documented in published patient reports and may potentially by certain L-shaped Type I ROS1 TKIs including gilteritinib which is approved as a FLT3 inhibitor for AML. Future clinical trials should investigate cabozantinib and gilteritinib to repurpose them as ROS1 TKIs that can target C?6 mutation.
- |||||||||| Qi Xinke (iruplinalkib) / Qilu Pharma
Journal, Metastases: Chinese expert consensus on iruplinalkib for the treatment of locally advanced or metastatic ALK-positive non-small cell lung cancer (2024 edition) (Pubmed Central) - Mar 22, 2024
On January 16, 2024, the NMPA approved iruplinalkib for the first-line treatment of locally advanced or metastatic ALK-positive NSCLC patients. In order to better understand the efficacy and safety of iruplinalkib, and facilitate more rationally clinical application of iruplinalkib, the Medical Oncology Branch of China International Exchange and Promotive Association for Medical and Health Care and the Chinese Association for Clinical Oncologists co-organized experts to compile the "Chinese expert consensus on iruplinalkib for the treatment of locally advanced or metastatic ALK-positive non-small cell lung cancer (2024 edition)".
- |||||||||| Enrollment closed, Enrollment change, IO biomarker, Metastases: MULTISARC: Molecular Profiling of Advanced Soft-tissue Sarcomas (clinicaltrials.gov) - Mar 5, 2024
P3, N=603, Active, not recruiting,
Overall, this study presents the added value of using spheroids and positions lorlatinib and repotrectinib as the most effective TKIs against the studied ROS1 resistance point mutations. Recruiting --> Active, not recruiting | N=960 --> 603
- |||||||||| Interrogation of autophagy inhibition in anaplastic large cell lymphoma (ALCL) (Section 14) - Mar 5, 2024 - Abstract #AACR2024AACR_7051;
With the addition of crizotinib or brentuximab vedotin to the ALCL99 chemotherapy backbone, the recently reported Children's Oncology Group ANHL12P1 study demonstrated a 2-year event-free survival for ALCL patients of 79%...Target engagement of autophagy inhibition (ULK-101 directed against ULK1/2 and hydroxychloroquine (HCQ) targeting the lysosome) was assessed by western blot using phospho-ATG14S29 and LC3B-II intensity in 6-point dose response curves...Decreased viability in Karpas 299 cells was observed after crizotinib, ceritinib and lorlatinib treatments with nanomolar potency...ALK inhibition activates autophagy in ALCL cells and autophagy activation is effectively mitigated through concurrent autophagy inhibition. ALK inhibitor resistance in Karpas 299 cells will be further evaluated to determine whether autophagy contributes to the resistant phenotype.
- |||||||||| Zykadia (ceritinib) / Novartis, Mekinist (trametinib) / Novartis, BeiGene
Phase 1/2 trial of trametinib + ceritinib in patients with unresectable melanoma (Section 48) - Mar 5, 2024 - Abstract #AACR2024AACR_3857;
These results highlight potential disparities in the diagnosis and treatment of ROS1+ NSCLC and opportunities for improving clinical outcomes. Abstract is embargoed at this time.
- |||||||||| Zykadia (ceritinib) / Novartis
Journal: Environment-Sensitive Fluorescent Probe Enables Assessment of Anaplastic Lymphoma Kinase Activity in Nonsmall Cell Lung Cancer. (Pubmed Central) - Feb 28, 2024
HX16 is a multifunctional chemical tool based on the pharmacophore of ALK-TKI (ceritinib) and can specifically target the kinase domain of ALK with a high sensitivity...Importantly, HX16 was also applied to visualize ALK activity in a tumor biopsy from a NSCLC patient with ALK-echinoderm microtubule-associated protein-like-4 fusion gene for prediction of ALK-TKI sensitivity. These results demonstrate that strategically designed ALK-TKI-based probe allows the assessment of ALK activity in tumor tissues and hold promise as a useful diagnostic tool in predicting ALK-TKI therapy response.
- |||||||||| Zykadia (ceritinib) / Novartis
Journal: Therapeutic Implications of Ceritinib in Cholangiocarcinoma beyond ALK Expression and Mutation. (Pubmed Central) - Feb 24, 2024
Standard chemotherapy involves gemcitabine-based therapies combined with cisplatin, oxaliplatin, capecitabine, or 5-FU with a dismal prognosis for most patients...Additionally, ceritinib and cisplatin synergistically reduced CCA cell viability. Our data show ceritinib as an effective treatment of CCA, which could be potentially explored in the other cancer types without ALK mutations.
- |||||||||| Journal, Metastases: China expert recommendations on anaplastic lymphoma kinase-tyrosine kinase inhibitors treatment for advanced non-small cell lung cancer (2024 edition) (Pubmed Central) - Feb 10, 2024
To standardize the application of ALK-TKI, the Chinese Association for Clinical Oncologists and the Medical Oncology Branch of China International Exchange and Promotive Association for Medical and Health Care has organized experts to compile the " China expert recommendations on anaplastic lymphoma kinase-tyrosine kinase inhibitors treatment for advanced non-small cell lung cancer (2024 edition)". This treatment expert recommendation provides recommendations in four aspects, encompassing ALK fusion testing, ALK-TKI targeted therapy, ALK-TKI adverse events management, and patient post-treatment follow-up, thus serving as a valuable reference for the standardized treatment of Chinese advanced ALK fusion-positive NSCLC.
- |||||||||| Zykadia (ceritinib) / Novartis
Journal: A small-molecule degrader selectively inhibits the growth of ALK-rearranged lung cancer with ceritinib resistance. (Pubmed Central) - Feb 8, 2024
This treatment expert recommendation provides recommendations in four aspects, encompassing ALK fusion testing, ALK-TKI targeted therapy, ALK-TKI adverse events management, and patient post-treatment follow-up, thus serving as a valuable reference for the standardized treatment of Chinese advanced ALK fusion-positive NSCLC. Furthermore, dEALK1 also exerts a potent antitumor activity against EML4-ALK-positive xenograft tumors without or with harboring ceritinib-resistant EML4-ALK mutations in
- |||||||||| Lorbrena (lorlatinib) / Pfizer
Review, Journal: From Development to Place in Therapy of Lorlatinib for the Treatment of ALK and ROS1 Rearranged Non-Small Cell Lung Cancer (NSCLC). (Pubmed Central) - Jan 11, 2024
So, when prescribing lorlatinib, clinicians must face two diametrically opposed characteristics: a great therapeutic potential without the intrinsic limitations of its precursor TKIs, a cytotoxic activity threatened by suboptimal tolerability, and the unavoidable onset of resistance mechanisms we cannot properly manage yet. In this paper, we give a critical point of view on the stepwise introduction of this promising drug into clinical practice, starting from its innovative molecular and biochemical properties to intriguing future developments, without forgetting its weaknesses.
- |||||||||| batoprotafib (TNO155) / Novartis
Journal: SHP2 inhibition with TNO155 increases efficacy and overcomes resistance of ALK inhibitors in neuroblastoma. (Pubmed Central) - Jan 2, 2024
Finally, we show that lorlatinib-resistant ALK-F1174L neuroblastoma cells harbor additional RAS-MAPK pathway alterations and can be re-sensitized to lorlatinib when combined with TNO155 in vitro and in vivo. Our results report the first evaluation of TNO155 in neuroblastoma and suggest that combinatorial inhibition of ALK and SHP2 could be a novel approach to treating ALK-driven neuroblastoma, potentially including the increasingly common tumors that have developed resistance to ALK-TKIs.
- |||||||||| Xalkori (crizotinib) / Pfizer, Zykadia (ceritinib) / Novartis, Tabrecta (capmatinib) / Incyte, Novartis
Preclinical, Journal: Preclinical evidence for anaplastic lymphoma kinase inhibitors as novel therapeutic treatments for cholangiocarcinoma. (Pubmed Central) - Dec 25, 2023
Our results report the first evaluation of TNO155 in neuroblastoma and suggest that combinatorial inhibition of ALK and SHP2 could be a novel approach to treating ALK-driven neuroblastoma, potentially including the increasingly common tumors that have developed resistance to ALK-TKIs. Whereas capmatinib did not affect cell survival, ceritinib dose-dependently inhibited survival in all cell lines, with IC ranging from 1 to 9
- |||||||||| Zykadia (ceritinib) / Novartis
Journal: Safety and Effectiveness of Zykadia (Pubmed Central) - Dec 5, 2023
The median progression- free survival was approximately 4 months. The safety and efficacy were similar to those of previous reports, and this study confirmed that there are no problems requiring additional precautions in clinical use of Zykadia
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