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| Ref Type | Journal Article | ||||||||||||
| PMID | (30978502) | ||||||||||||
| Authors | Michels S, Massutí B, Schildhaus HU, Franklin J, Sebastian M, Felip E, Grohé C, Rodriguez-Abreu D, Abdulla DSY, Bischoff H, Brandts C, Carcereny E, Corral J, Dingemans AC, Pereira E, Fassunke J, Fischer RN, Gardizi M, Heukamp L, Insa A, Kron A, Menon R, Persigehl T, Reck M, Riedel R, Rothschild SI, Scheel AH, Scheffler M, Schmalz P, Smit EF, Limburg M, Provencio M, Karachaliou N, Merkelbach-Bruse S, Hellmich M, Nogova L, Büttner R, Rosell R, Wolf J | ||||||||||||
| Title | Safety and Efficacy of Crizotinib in Patients With Advanced or Metastatic ROS1-Rearranged Lung Cancer (EUCROSS): A European Phase II Clinical Trial. | ||||||||||||
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| Abstract Text | ROS1 rearrangements are found in 1% of lung cancer patients. Therapeutic efficacy of crizotinib in this subset has been shown in early phase trials in the United States and East Asia. Here we present data on efficacy and safety of a prospective phase II trial evaluating crizotinib in European ROS1-positive patients (EUCROSS).The trial was a multicenter, single-arm phase II trial (Clinicaltrial.gov identifier: NCT02183870). Key eligibility criteria included patients who were 18 years of age or older with advanced/metastatic lung cancer and centrally confirmed ROS1-rearranged lung cancer (fluorescence-in situ hybridization). Treatment included 250 mg crizotinib twice daily. The primary endpoint was investigator-assessed objective response rate (ORR) (Response Evaluation Criteria in Solid Tumors, version 1.1). Key secondary endpoints were progression-free survival (PFS), overall survival, efficacy by independent radiologic review, safety, health-related quality of life, and molecular characterization of tumor tissue.Thirty-four patients received treatment. Four patients were excluded from efficacy analysis. Investigator ORR was 70% (95% confidence interval [CI]: 51-85; 21 of 30 patients) and median PFS was 20.0 months (95% CI: 10.1-not reached). Two patients with ROS1 wild-type sequences assessed by DNA sequencing had progression as best response. CD74-ROS1-positive patients had a trend towards a higher ORR and longer median PFS. TP53-co-mutant patients had a significantly shorter median PFS than wild-type patients (7.0 months, 95% CI: 1.7-20.0 versus 24.1 months, 95% CI: 10.1-not reached; p = 0.022). Treatment-related adverse events were documented in 33 of 34 patients (97%).Crizotinib is highly effective and safe in patients with ROS1-rearranged lung cancer. ROS1-/TP53-co-aberrant patients had a significantly worse outcome compared to TP53 wild-type patients. | ||||||||||||
| Molecular Profile | Treatment Approach |
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| Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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| Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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| Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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| Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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| TP53 | P278H | missense | unknown | TP53 P278H lies within the DNA-binding domain of the Tp53 protein (PMID: 15510160). P278H has been identified in the scientific literature (PMID: 27022024, PMID: 25151357, PMID: 30978502), but has not been biochemically characterized and therefore, its effect on Tp53 protein function is unknown (PubMed, Feb 2024). |
| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| ROS1 rearrange PIK3CA E545K | lung non-small cell carcinoma | predicted - resistant | Crizotinib | Case Reports/Case Series | Actionable | In a Phase II clinical trial, a patient with non-small cell lung cancer harboring a ROS1 rearrangement demonstrated progression while being treated with Xalkori (crizotinib), and was found to have acquired a PIK3CA E545K mutation (PMID: 30978502; NCT02183870). | 30978502 |
| ROS1 rearrange ROS1 L2026M TP53 P278H | lung non-small cell carcinoma | predicted - resistant | Crizotinib | Case Reports/Case Series | Actionable | In a Phase II clinical trial, a patient with non-small cell lung cancer harboring a ROS1 rearrangement demonstrated progression while being treated with Xalkori (crizotinib), and was found to have acquired two mutations, ROS1 L2026M and TP53 P278H (PMID: 30978502; NCT02183870). | 30978502 |
| ROS1 rearrange TP53 mut | lung non-small cell carcinoma | predicted - sensitive | Crizotinib | Clinical Study - Cohort | Actionable | In a Phase II clinical trial, treatment with Xalkori (crizotinib) demonstrated a shorter median progression-free survival in patients with non-small cell lung cancer co-harboring a ROS1 rearrangement and TP53 mutation compared to patients with a ROS1 rearrangement and wild-type TP53 (7 vs. 24.1 months; p=0.022) (PMID: 30978502; NCT02183870). | 30978502 |
| ROS1 rearrange | lung non-small cell carcinoma | sensitive | Crizotinib | Phase II | Actionable | In a Phase II clinical trial, patients with non-small cell lung cancer harboring a ROS1 rearrangement demonstrated an objective response rate of 70% (21/30; all partial response), a median progression-free survival (PFS) of 20 months, a duration of response of 19 months, and a survival rate of 83% at 12 months and 63% at 24 months, when treated with Xalkori (crizotinib) (PMID: 30978502; NCT02183870). | 30978502 |