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• W2892133082 abstract "The gene ROS1 is a tyrosine kinase receptor that becomes constitutively expressed when fused with a partner gene, most commonly CD molecule 74 gene (CD74).1Herbst R.S. Morgensztern D. Boshoff C. The biology and management of non-small cell lung cancer.Nature. 2018; 553: 446Crossref PubMed Scopus (1935) Google Scholar In ROS1-positive NSCLC, tyrosine kinase inhibitors (TKIs) are now used as first-line agents, with median progression-free survival (PFS) ranging from 10 to 19 months.2Dagogo-Jack I. Shaw A.T. Expanding the roster of ROS1 inhibitors.J Clin Oncol. 2017; 35: 2595-2597Crossref Scopus (15) Google Scholar Crizotinib is currently the only approved agent, but ceritinib appears to have similar efficacy and better intracranial activity.2Dagogo-Jack I. Shaw A.T. Expanding the roster of ROS1 inhibitors.J Clin Oncol. 2017; 35: 2595-2597Crossref Scopus (15) Google Scholar, 3Lim S.M. Kim H.R. Lee J.S. et al.Open-label, multicenter, phase II study of ceritinib in patients with non-small-cell lung cancer harboring ROS1 rearrangement.J Clin Oncol. 2017; 35: 2613-2618Crossref PubMed Scopus (229) Google Scholar However, once resistance to crizotinib or ceritinib develops in a patient, TKI treatment options become limited. Next-line therapy, platinum- and pemetrexed-based chemotherapy, provides a median PFS of only 7 months.4Mazieres J. Zalcman G. Crino L. et al.Crizotinib therapy for advanced lung adenocarcinoma and a ROS1 rearrangement: results from the EUROS1 cohort.J Clin Oncol. 2015; 33: 992-999Crossref PubMed Scopus (291) Google Scholar Here, we report four patients who experienced development of secondary resistance to crizotinib followed by primary resistance to ceritinib and were then treated with cabozantinib. A 70-year-old man with a minimal smoking history presented with stage 3b (T1N3M0) NSCLC. His disease progressed despite radiation concurrently with carboplatin and paclitaxel and later with cisplatin, pemetrexed, and bevacizumab. Two years after diagnosis, he began taking crizotinib after interphase fluorescence in situ hybridization (FISH) revealed ROS1 gene rearrangement. He had disease progression 11.2 months later, and in 2015, he was given ceritinib instead of crizotinib but continued to have disease progression (Table 1). He was enrolled in a phase I trial of an investigational TKI but had progression and subsequently began receiving cabozantinib (40 mg off label), during which time he achieved a partial response after 6.5 months. Subsequently, he had enlarging nontarget lesions and his dose of cabozantinib was escalated to 40 and 60 mg on alternating days. He had been receiving cabozantinib for a total of 13.8 months before disease progression (Fig. 1). The only treatment-related adverse event was mild neutropenia that self-resolved after 4 months.Table 1Summary of Cases, Including Progression-Free Survival during Cabozantinib Therapy and Disease Control RateCaseCrizotinib Therapy, moCeritinib TherapyCabozantinib TherapyPFS with Cabozantinib TherapyBrain Metastases with Cabozantinib TherapyBest Overall Response RateDisease Control RateObjective Response Rate17.92.118.313.8—Partial response100%25%212.41.45.14.9Non-CR/non-PD (for ≥4.9 mo)aPatient died of an unrelated cause.Stable disease310.62.914.5bPatient continues to receive this therapy.7.4Stable disease (stable for ≥14.5 mo)Stable disease435.1bPatient continues to receive this therapy.—2.2cTherapy stopped because of side effects.——Stable diseaseCR, complete response; PD, progressive disease; PFS, progression-free survival; Non-CR/non-PD, neither a complete response nor progressive disease.a Patient died of an unrelated cause.b Patient continues to receive this therapy.c Therapy stopped because of side effects. Open table in a new tab CR, complete response; PD, progressive disease; PFS, progression-free survival; Non-CR/non-PD, neither a complete response nor progressive disease. A 45-year-old female never-smoker presented with stage 3a (T3N2M0) NSCLC and received radiation concurrently with carboplatin and paclitaxel. Fifteen months later, brain metastases developed and she received whole-brain radiation and carboplatin, paclitaxel, and bevacizumab. Upon disease progression, she began receiving crizotinib after FISH demonstrated ROS1 rearrangement. Thirteen months later, her brain metastases worsened, with the largest lesion measuring 12 mm. Her treatment was switched from crizotinib to ceritinib in 2015, but her brain metastases continued to progress, with the largest lesion measuring 19 mm. She then received a novel chemotherapeutic agent on a clinical trial and subsequently received pemetrexed, bevacizumab, and stereotactic radiation to four brain lesions. Seven months later, upon worsening intracranial and systemic disease, she began receiving cabozantinib, 40 mg. Upon the start of cabozantinib therapy, two small frontal lobe lesions resolved, one lesion decreased from 4 to 3 mm, one lesion decreased from 4 to 2 mm, and two other lesions remained stable (Fig. 2). The patient had 4.9 months of stable disease while taking cabozantinib before progression of her lung nodules, and she died of unrelated causes. The treatment-related adverse events were grade 1 xeroderma and pulmonary embolism. A 52-year-old man with a minimal smoking history presented with stage 4 (T4N3M1b) NSCLC that was metastatic to the brain, bone, and muscle. He received cisplatin, pemetrexed, and stereotactic radiation to four brain lesions. Upon disease progression in the lungs and the brain, he began receiving crizotinib after ROS1 rearrangement was identified by FISH. Ten months later (after disease progression in the brain and muscle), the patient's treatment was changed to ceritinib in early 2017 but his disease in these sites continued to worsen (with the largest brain lesion measuring 16 mm). He began receiving cabozantinib, 40 mg, during which time he was able to achieve systemic and intracranial stable disease for 7.4 months before oligoprogression in two pulmonary masses. He received stereotactic ablative radiotherapy to these lesions with an excellent response. He has continued to take cabozantinib for nearly 15 months with stable brain metastases. The only treatment-related adverse event was grade 1 hyperkeratosis. A 68-year-old female never-smoker presented with stage 4 (T2aN2M1b) NSCLC metastatic to bone. She received carboplatin, pemetrexed, and radiation to lung and sternal masses. Upon disease progression, she began receiving crizotinib after testing positive for ROS1 by FISH. Thirty-five months later, her lung disease and respiratory symptoms worsened and she began receiving cabozantinib, 40 mg. Three weeks later, the dose was reduced to 20 mg secondary to grade 2 lightheadedness. Two months later she had stable disease but stopped therapy because of continued lightheadedness and pulmonary embolism. She was switched back to crizotinib given her prior good tolerance of it and very slow disease progression while taking it. Crizotinib and ceritinib are effective first-line treatments for ROS1-positive NSCLC.2Dagogo-Jack I. Shaw A.T. Expanding the roster of ROS1 inhibitors.J Clin Oncol. 2017; 35: 2595-2597Crossref Scopus (15) Google Scholar Unfortunately, unlike for ALK receptor tyrosine kinase gene (ALK) or EGFR-positive NSCLC, there is no approved second-line targeted therapy that can be offered over chemotherapy once resistance develops. The data regarding ceritinib as a second-line TKI are very limited and conflicting, with a report of a partial response seen in one patient but disease progression in a separate report on two patients.3Lim S.M. Kim H.R. Lee J.S. et al.Open-label, multicenter, phase II study of ceritinib in patients with non-small-cell lung cancer harboring ROS1 rearrangement.J Clin Oncol. 2017; 35: 2613-2618Crossref PubMed Scopus (229) Google Scholar, 5Subbiah V. Hong D.S. Meric-Bernstam F. Clinical activity of ceritinib in ROS1-rearranged non-small cell lung cancer: bench to bedside report.Proc Natl Acad Sci U S A. 2016; 113: E1419-E1420Crossref PubMed Scopus (30) Google Scholar In our three patients who received second-line ceritinib, it was ineffective in controlling systemic and intracranial disease despite its efficacy in the first-line setting. Prior studies have found that ceritinib and entrectinib are not effective in treating crizotinib-resistant patients but lorlatinib may be.3Lim S.M. Kim H.R. Lee J.S. et al.Open-label, multicenter, phase II study of ceritinib in patients with non-small-cell lung cancer harboring ROS1 rearrangement.J Clin Oncol. 2017; 35: 2613-2618Crossref PubMed Scopus (229) Google Scholar, 6Drilon A. Siena S. Ou S.I. et al.Safety and antitumor activity of the multitargeted pan-TRK, ROS1, and ALK inhibitor entrectinib: combined results from two phase I trials (ALKA-372-001 and STARTRK-1).Cancer Disc. 2017; 7: 400-409Crossref PubMed Scopus (545) Google Scholar, 7Shaw A.T. Felip E. Bauer T.M. et al.Lorlatinib in non-small-cell lung cancer with ALK or ROS1 rearrangement: an international, multicentre, open-label, single-arm first-in-man phase 1 trial.Lancet Oncol. 2017; 18: 1590-1599Abstract Full Text Full Text PDF PubMed Scopus (452) Google Scholar Preclinical data, and two single-patient case reports, have suggested that cabozantinib can be effective in such patients by binding to ROS1 despite resistant solvent front mutation.8Drilon A. Somwar R. Wagner J.P. et al.A novel crizotinib-resistant solvent-front mutation responsive to cabozantinib therapy in a patient with ROS1-rearranged lung cancer.Clin Cancer Res. 2016; 22: 2351-2358Crossref PubMed Scopus (122) Google Scholar, 9Chong C.R. Bahcall M. Capelletti M. et al.Identification of existing drugs that effectively target NTRK1 and ROS1 rearrangements in lung cancer.Clin Cancer Res. 2017; 23: 204-213Crossref PubMed Scopus (64) Google Scholar, 10Katayama R. Kobayashi Y. Friboulet L. et al.Cabozantinib overcomes crizotinib resistance in ROS1 fusion-positive cancer.Clin Cancer Res. 2015; 21: 166-174Crossref PubMed Scopus (152) Google Scholar, 11Davare M.A. Vellore N.A. Wagner J.P. et al.Structural insight into selectivity and resistance profiles of ROS1 tyrosine kinase inhibitors.Proc Natl Acad Sci U S A. 2015; 112: E5381-E5390Crossref PubMed Scopus (81) Google Scholar Here, we have reported four patients who received cabozantinib and achieved a disease control rate of 100%, objective response rate of 25%, and PFS time ranging from 4.9 to 13.8 months (Table 1). To our knowledge, we are reporting for the first time the efficacy of cabozantinib in patients with primary ceritinib resistance and its apparent intracranial activity in patients with secondary crizotinib resistance and primary ceritinib resistance. Patient 3, for example, had longer stable brain metastases on cabozantinib than on crizotinib or ceritinib. Because of a lack of tissue, we were unable to characterize the crizotinib resistance mutations that developed in these four patients and were ultimately susceptible to cabozantinib. It is encouraging that regardless of the respective mutation that developed in each of the four patients, they all responded to cabozantinib." @default.
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• W2892133082 title "Lengthy Progression-Free Survival and Intracranial Activity of Cabozantinib in Patients with Crizotinib and Ceritinib-Resistant ROS1-Positive Non–Small Cell Lung Cancer" @default.
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