- |||||||||| Xalkori (crizotinib) / Pfizer
INFLAMMATORY MYOFIBROBLAST TUMOR OF LUNG: A RARE FIND IN AN ELDERLY FEMALE (Convention Center Exhibit Hall: Poster Area 3) - Jul 31, 2024 - Abstract #CHEST2024CHEST_5498;
IMTs present a multifaceted challenge in clinical practice due to their diverse clinical manifestations, histopathological variability, and unclear etiopathogenesis despite progress in identifying fusion protein-driven mechanisms: continued research efforts are needed, and a multidisciplinary approach is necessary to optimize patient outcomes. Clinicians should consider IMT in the broad differential of lung lesions.
- |||||||||| Xalkori (crizotinib) / Pfizer, Entresto (sacubitril/valsartan) / Novartis, ROVI Pharmaceuticals Laboratories
Preclinical, Journal: Sacubitril/Valsartan Ameliorates Crizotinib-Induced Cardiotoxicity in Mice. (Pubmed Central) - Jul 30, 2024
Crizotinib induced a range of cardiotoxic side effects in a mouse model and increased Myh7 expression represents a biomarker for this response. These cardiovascular toxic responses can be largely prevented by sacubitril/valsartan.
- |||||||||| MET Fusions in NSCLC: Prevalence, Oncogenicity, and Resistance Mechanism (Exhibit Hall) - Jul 24, 2024 - Abstract #IASLCWCLC2024IASLC_WCLC_2507;
Within the DFCI cohort, a MET fusion was detected after targeted therapy in other oncogene-driven NSCLC (1 case of ALK fusion-positive NSCLC after alectinib and crizotinib treatment; and 1 case of EGFR -mutant NSCLC after osimertinib treatment), suggesting the potential implication of MET fusion in conferring resistance to targeted therapy in the setting of other oncogene-driven NSCLC...The MET D1228V mutation led to resistance to type I MET TKIs (i.e. crizotinib, APL-101, capmatinib, tepotinib)...Similar to NSCLC with MET exon 14 skipping alterations, a mutation in the kinase domain of the MET fusion could conferred resistance to a MET TKI. Additionally, MET fusions were detected at resistance after targeted therapy for other oncogene-driven NSCLC, with in vitro modeling showing that it could be overcome by combinatorial treatments with TKIs.
- |||||||||| 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
- |||||||||| Xalkori (crizotinib) / Pfizer
The Functional Roles of Intergenic ALK Fusions in NSCLC (Exhibit Hall) - Jul 24, 2024 - Abstract #IASLCWCLC2024IASLC_WCLC_1689;
The patient responded but rapidly relapsed to crizotinib treatment...Conclusions : Our study validated LA as a driver of NSCLC, which might be less responsive to ALK inhibitors. Thus, LA should be included for future NSCLC diagnosis and better treatments for these patients should be developed.
- |||||||||| Xalkori (crizotinib) / Pfizer, Qi Xinke (iruplinalkib) / Qilu Pharma
Iruplinalkib in Patients with ALK-Positive Crizotinib-Resistant NSCLC: Updated Efficacy and Safety Data from a Phase 2 Trial (Exhibit Hall) - Jul 24, 2024 - Abstract #IASLCWCLC2024IASLC_WCLC_1602;
P2
The updated results provided new evidence for the use of iruplinalkib in patients with ALK-positive crizotinib-resistant advanced NSCLC. Investigator-assessed response in pts with measurable intracranial lesions and with CNS metastases Per investigator Patients with measurable intracranial lesions (n=42) Patients with central nervous system metastases (n=90) Best of response, n (%) Complete response 3 (7.1%) 0 Partial response 24 (57.1%) 50 (55.6%) Stable disease 13 (31.0%) 34 (37.8%) Progressive disease 1 (2.4%) 4 (4.4%) Not evaluable 1 (2.4%) 2 (2.2%) Objective response rate, n (%) 27 (64.3%) 50 (55.6%) 95% confidence interval 48.0% to 78.4% 44.7% to 66.0% Disease control rate, n (%) 40 (95.2%) 84 (93.3%) 95% confidence interval 83.8% to 99.4% 86.1% to 97.5% Median duration of response, months 18.69 17.25 95% confidence interval 15.01 to 20.99 10.35 to 19.48
- |||||||||| Lorbrena (lorlatinib) / Pfizer, TGRX-326 / Shenzhen TargetRx
Deulorlatinib (TGRX-326)in Patients with ALK Fusion-Positive NSCLC: Update from the Phase 1 Trial (Exhibit Hall) - Jul 24, 2024 - Abstract #IASLCWCLC2024IASLC_WCLC_1601;
P1, P2, P3
Based on these findings, 2 pivotal studies (NCT05955391/NCT06082635) are currently ongoing. Efficacy of deulorlatinib Cohort A1 n=14 Cohort A2 n=97 Cohort C n=33 ORR, % (95% CI) 71.4 (41.9-91.6) 39.2 (29.4-49.6) 87.9 (71.8-96.6) DCR, % (95% CI) 100 (79.8-100) 82.5 (73.4-89.5) 97.0 (84.2-99.9) Median DOR, months (95% CI) NA (11.8-NA) 18.0 (15.1-NA) NA (NA-NA) 12-month DOR estimate, % (95% CI) 90.0 (73.2-100) 73.3 (60.4-89.0) 88.9 (77.8-100) Median PFS, months (95% CI) NA (9.7-NA) 9.0 (5.7-16.8) NA (NA-NA) 12-month PFS estimate, % (95% CI) 74.1 (51.3-99.5) 47.5 (38.1-59.1) 78.5 (65.5-94.0) Median OS, months (95% CI) NA (NA-NA) NA (22.4-NA) NA (NA-NA) 12-month OS estimate, % (95% CI) 85.7 (69.2-100) 80.4 (72.9-88.7) 90.9 (81.6-100)
- |||||||||| Alunbrig (brigatinib) / Takeda
Real-World Outcomes of 2L ALK TKIs Following 1L Brigatinib for Patients with ALK+ NSCLC from the ALTA-1L Trial (Exhibit Hall) - Jul 24, 2024 - Abstract #IASLCWCLC2024IASLC_WCLC_1598;
Introduction : In the phase III ALTA-1L trial, brigatinib showed superior efficacy vs. crizotinib in first line (1L) for anaplastic lymphoma kinase positive ( ALK +) non-small cell lung cancer (NSCLC)...Of these, 30 received a 2L ALK TKI (median follow-up, 17.0 months; median age, 57.5 years; White, 46.7%; Asian, 50.0%; female, 60.0%), including 16 (53.3%) on 2L lorlatinib and 8 (26.7%) on 2L alectinib...This study was limited by small sample size. 1 Delmonte A. Poster #38P ELCC 2024
- |||||||||| Alecensa (alectinib) / Roche
Mechanisms of Resistance to First-Line vs Later-Line Alectinib in ALK Fusion-Positive Non-Small Cell Lung Cancer (Exhibit Hall) - Jul 24, 2024 - Abstract #IASLCWCLC2024IASLC_WCLC_1595;
Conclusions : In this largest series of alectinib-resistant biopsies to date, on-target resistance (i.e., ALK resistance mutation) was significantly less common when alectinib was used as 1L vs 2L+ therapy, highlighting the importance of elucidating strategies to overcome off-target resistance to next-generation ALK TKI. Our findings additionally underscore the complementary role of tissue and plasma re-biopsies in delineating the resistance landscape, with tissue more likely to detect MET amplification and capable of identifying histologic transformation and plasma more likely to detect ?2 co-occurring ALK mutations.
- |||||||||| Xalkori (crizotinib) / Pfizer, Tabrecta (capmatinib) / Novartis, Tepmetko (tepotinib) / EMD Serono
Outcome and Transcriptomic Features of Dual EGFR and MET Blockade in NSCLC (Exhibit Hall) - Jul 24, 2024 - Abstract #IASLCWCLC2024IASLC_WCLC_1586;
Other possible predictive factors are MET polysomy, high tumor content, and TRU subtype. We suggest further investigation to define MET amplification cut-off and patient selection based on responsiveness to EGFR TKI.
- |||||||||| Alecensa (alectinib) / Roche
Mechanisms of Resistance to First-Line vs Later-Line Alectinib in ALK Fusion-Positive Non-Small Cell Lung Cancer (Exhibit Hall) - Jul 24, 2024 - Abstract #IASLCWCLC2024IASLC_WCLC_1579;
Conclusions : In this largest series of alectinib-resistant biopsies to date, on-target resistance (i.e., ALK resistance mutation) was significantly less common when alectinib was used as 1L vs 2L+ therapy, highlighting the importance of elucidating strategies to overcome off-target resistance to next-generation ALK TKI. Our findings additionally underscore the complementary role of tissue and plasma re-biopsies in delineating the resistance landscape, with tissue more likely to detect MET amplification and capable of identifying histologic transformation and plasma more likely to detect ?2 co-occurring ALK mutations.
- |||||||||| Xalkori (crizotinib) / Pfizer, Tabrecta (capmatinib) / Novartis, Tagrisso (osimertinib) / AstraZeneca
Comprehensive Pan-Cancer Analysis of Oncogenic MET Rearrangements with a Focus on Targetability in NSCLC (Exhibit Hall) - Jul 24, 2024 - Abstract #IASLCWCLC2024IASLC_WCLC_1485;
We also describe a cohort of patients with acquired MET fusions as a resistance mechanism to different targeted therapies. Our findings provide further support for clinical trial evaluation of MET inhibitors in MET fusion driven cancers, particularly NSCLC.
- |||||||||| Ensacove (ensartinib) / Betta Pharma
Predictors of Long-Term Ensartinib Response from the eXalt3 Trial (20D) - Jul 24, 2024 - Abstract #IASLCWCLC2024IASLC_WCLC_980;
Conclusions : We profiled three patients who have continued to respond to ensartinib for over 70 cycles, despite exhibiting clinically validated resistance mechanisms to other ALK inhibitors at enrollment. The REvolution, long-term evolution system, identified biomarkers which predicted response to ensartinib.
- |||||||||| Lorbrena (lorlatinib) / Pfizer
Kinetics and Management of Adverse Events Associated with Lorlatinib after 5 Years of Follow-Up in the CROWN Study (20D) - Jul 24, 2024 - Abstract #IASLCWCLC2024IASLC_WCLC_979;
P3
Systemic and intracranial outcomes in patients who underwent dose reduction were similar to those in patients who did not undergo dose reduction, indicating that dose reductions may be an effective strategy to mitigate toxicity without compromising efficacy of lorlatinib. ClinicalTrials.gov NCT03052608 Table Incidence and prevalence of CNS AEs Time interval n Incidence, n (%) Prevalence, n (%) 0-6 months 149 37 (25) 37 (25) 6 months-1 year 129 14 (11) 28 (22) 1-2 years 117 17 (15) 32 (27) 2-3 years 98 12 (12) 26 (27) 3-4 years 90 7 (8) 23 (26) 4-5 years 84 9 (11) 22 (26) ?5 years 79 1 (1) 9 (11) Time to onset and duration of most common AEs that led to dose reduction or interruption AEs n Time to onset, median (range), days Duration of AE, median (range), days Hypercholesterolemia 108 14 (1-1205) 1093 (14-2256) Hypertriglyceridemia 99 15 (6-973) 1151 (23-2247) Edema 85 54 (1-1503) 366 (4-2045) Peripheral neuropathy 65 113 (2-1784) 546 (7-1990) CNS AEs 63 116 (1-1657) 237 (2-2071)
- |||||||||| 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
- |||||||||| Xalkori (crizotinib) / Pfizer
Journal, PD(L)-1 Biomarker, IO biomarker: Case report: Pulmonary sarcomatoid carcinoma demonstrating rapid growth on follow-up CT. (Pubmed Central) - Jul 23, 2024
The patient was discharged with oral crizotinib targeted therapy, and his condition remained stable postoperatively...Pulmonary sarcomatoid carcinoma can exhibit rapid tumor growth on imaging, and PSC should be considered in the differential diagnosis for lesions that present with a fast growth rate. Timely and appropriate treatment for PSC may lead to a good prognosis.
- |||||||||| Xalkori (crizotinib) / Pfizer
Review, Journal, BRCA Biomarker, PARP Biomarker: Overcoming Chemoresistance in Cancer: The Promise of Crizotinib. (Pubmed Central) - Jul 13, 2024
In summary, crizotinib exerts anti-tumor effects through several mechanisms, including the inhibition of kinases and the restoration of drug sensitivity. The potential of crizotinib in combination therapies is emphasized, particularly in cancers with a high prevalence of the p53 mutant, such as triple-negative breast cancer (TNBC) and high-grade serous ovarian cancer (HGSOC).
- |||||||||| Xalkori (crizotinib) / Pfizer
Review, Journal, IO biomarker: Inflammatory myofibroblastic tumor from molecular diagnostics to current treatment. (Pubmed Central) - Jul 1, 2024
Crizotinib, an ALK tyrosine kinase inhibitor (TKI), was officially approved by the US Food and Drug Administration (FDA) in 2020 to treat IMT with ALK rearrangement...However, defined recommendations are still lacking. This review analyzes the available research on IMT, including genetic disorders and their impact on the course of the disease, data on the latest targeted therapy regimens and the possibility of developing immunotherapy in this indication, as well as summarizing general knowledge about prognostic and predictive factors, also in terms of resistance to systemic therapy.
- |||||||||| Lorbrena (lorlatinib) / Pfizer, Xalkori (crizotinib) / Pfizer
Trial completion, Metastases: Proof of concept trial alternating lorlatinib with crizotinib in patients with anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (EUDRACT) - Jun 28, 2024
P1/2, N=25, Completed,
This review analyzes the available research on IMT, including genetic disorders and their impact on the course of the disease, data on the latest targeted therapy regimens and the possibility of developing immunotherapy in this indication, as well as summarizing general knowledge about prognostic and predictive factors, also in terms of resistance to systemic therapy. Active, not recruiting --> Completed
- |||||||||| Xalkori (crizotinib) / Pfizer
Enrollment closed, Enrollment change, Trial completion date, Trial primary completion date: Crizotinib Continuation Clinical Study (clinicaltrials.gov) - Jun 25, 2024
P4, N=26, Active, not recruiting,
In conclusion, the antineoplastic activity of crizotinib has been shown in human pATCs (with STRN-ALK) in preclinical studies in vitro, opening the way to future clinical evaluation in these patients. Recruiting --> Active, not recruiting | N=80 --> 26 | Trial completion date: Dec 2026 --> Mar 2028 | Trial primary completion date: Dec 2026 --> Mar 2028
- |||||||||| Xalkori (crizotinib) / Pfizer, Kimmtrak (tebentafusp-tebn) / Immunocore, darovasertib (IDE196) / Ideaya Biosci
Journal, Tumor mutational burden, Metastases: The Current State of Systemic Therapy of Metastatic Uveal Melanoma. (Pubmed Central) - Jun 22, 2024
Further, promising data from targeted therapies independent of MEK-inhibitors, such as the combination of darovasertib and crizotinib, raise hope for additional options in metastatic UM in the future. This narrative review provides a timely and comprehensive overview of the current treatment landscape for metastatic UM.
- |||||||||| Xalkori (crizotinib) / Pfizer
Journal: Integrating Ataxia Evaluation into Tumor-Induced Hearing Loss Model to Comprehensively Study NF2-Related Schwannomatosis. (Pubmed Central) - Jun 19, 2024
We further demonstrated that (i) treatment with anti-VEGF resulted in tumor size reduction, mitigated ataxia, and improved rotarod performance; (ii) treatment with crizotinib stabilized tumor growth and led to improvements in both ataxia and rotarod performance; and (iii) treatment with losartan did not impact tumor growth nor ameliorate ataxia or motor function. Our studies demonstrated that these methods, paired with hearing tests, enable a comprehensive evaluation of tumor-induced neurological deficits and facilitate the assessment of the effectiveness of novel therapeutics to improve NF2 treatments.
- |||||||||| Xalkori (crizotinib) / Pfizer
Journal, Metastases: Population modeling analyses of crizotinib in pediatric patients with ALK-positive advanced cancers. (Pubmed Central) - Jun 13, 2024
None of the myelosuppressive events except Grade ?3 NEUTROPENIA had significant relationships identified with crizotinib dose or exposure, suggesting crizotinib is a tolerable treatment with less hematological toxicity than traditional chemotherapy regimens for pediatric patients with ALK-mutated cancers. Results from the presented analyses support the pediatric dosing recommendations in the product label.
- |||||||||| Tabrecta (capmatinib) / Incyte, Novartis
Journal: Capmatinib is an effective treatment for MET-fusion driven pediatric high-grade glioma and synergizes with radiotherapy. (Pubmed Central) - Jun 8, 2024
Our seminal preclinical data package includes pharmacokinetic characterization, recapitulation of clinical outcomes, coinciding results from multiple complementing in vivo studies, and insights into molecular mechanism underlying increased efficacy. Taken together, we demonstrate the groundbreaking efficacy of capmatinib and radiation as a highly promising concept for future clinical trials.
- |||||||||| Xalkori (crizotinib) / Pfizer, Qi Xinke (iruplinalkib) / Qilu Pharma
P3 data, P3 data: top line, Journal, Metastases: Iruplinalkib (WX-0593) versus crizotinib in ALK TKI-na (Pubmed Central) - Jun 8, 2024
P3
Iruplinalkib was found to have significantly improved PFS and improved intracranial antitumor activity versus crizotinib. Iruplinalkib may be a new treatment option for patients with advanced ALK-positive and ALK TKI-naive NSCLC.
- |||||||||| Xalkori (crizotinib) / Pfizer, Rozlytrek (entrectinib) / Roche
Review, Journal: Lung cancer oncogene-directed therapy, fertility and pregnancy. (Pubmed Central) - Jun 8, 2024
Additional explorations of the impact and optimal timing of targeted therapy in egg capture and pregnancy are needed. Wider scientific and societal discussion about the issues of reproduction in advanced NSCLC is warranted.
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