Rapid‐onset hypogonadism secondary to crizotinib use in men with metastatic nonsmall cell lung cancer

Weickhardt, Andrew; Rothman, Micol S.; Salian-Mehta, Smita; Kiseljak-Vassiliades, Katja; Oton, Ana B.; Doebele, Robert C.; Wierman, Margaret E.; Camidge, D. Ross

doi:10.1002/cncr.27450

Cited by 88 publications

(76 citation statements)

References 47 publications

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“…11 Our analysis did not reveal any significant difference in the HR parameters examined and the clinical response to crizotinib between men and women. Thus, decrease in testosterone level is unlikely to be a mechanism that accounts for the HR decrease associated with the receipt of crizotinib.…”

Section: Discussioncontrasting

confidence: 50%

Heart rate decrease during crizotinib treatment and potential correlation to clinical response

Tong

Azada

et al. 2013

Cancer

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BACKGROUND:Crizotinib is used for the treatment of advanced anaplastic lymphoma kinase (ALK)-rearranged nonsmall cell lung cancer (NSCLC). Sinus bradycardia (SB) is a side effect listed in its package insert. We investigated the frequency and timing of SB, patient characteristics associated with SB during crizotinib treatment, and potential correlation between heart rate (HR) changes and clinical response to crizotinib. METHODS: A retrospective chart review was conducted of the timing and frequency of SB, patient characteristics, and clinical response of patients to crizotinib treatment. RESULTS: Forty-twp patients who had ALK-rearranged or mesenchymal epithelial transition (MET)-amplified NSCLC and received treatment with oral crizotinib 250 mg twice daily who were enrolled in 2 crizotinib trials (PROFILE 1001 and PROFILE 1005) were analyzed. There was an average decrease of 26.1 beats per minute (bpm) from the pretreatment HR among all patients during crizotinib treatment. Twenty-nine patients (69%) experienced at least 1 episode of SB (HR, <60 bpm). The average time to the lowest HR recorded was 18.6 weeks (range, 5-72 weeks). Patients who experienced SB were significantly older (aged 55.8 years vs 47.8 years; P ¼ .0336), had a lower pretreatment HR (mean, 77.9 bpm vs 100.6 bpm; P ¼ .002), and were on crizotinib longer (52.9 weeks vs 24.6 weeks; P ¼ .0050) than patients who did not experience SB. The overall response rate (P ¼ .0195) and the maximum tumor shrinkage (P ¼ .0205) were significantly greater in patients who experienced SB. CONCLUSIONS: HR decrease is common during crizotinib treatment. It remains to be determined whether the correlation between HR decrease and clinical response to crizotinib reflects a biomarker of drug efficacy or a time/cumulative dose-dependent phenomenon. Cancer 2013;119:1969-75. V C 2013 American Cancer Society.KEYWORDS: crizotinib, sinus bradycardia, heart rate decrease, pharmacodynamic, receptor tyrosine kinase inhibitor, anaplastic lymphoma kinase (ALK)-rearranged nonsmall cell lung cancer. INTRODUCTIONCrizotinib is a first-in-class, orally available anaplastic kinase (ALK) inhibitor that has exhibited impressive clinical activity in ALK-rearranged nonsmall cell lung cancer (NSCLC) in 2 phase 2, single-arm clinical trials. [1][2][3] It has also demonstrated significantly improved progression-free survival (PFS) over single-agent chemotherapy as second-line treatment for patients with ALK-rearranged NSCLC in a randomized phase 3 trial. 4 Crizotinib has been approved in many countries for the treatment of ALK-rearranged NSCLC. In addition, as a multitargeted receptor tyrosine kinase (RTK) inhibitor that also can inhibit both the mesenchymal epithelial transition (MET) and ROS1 receptor tyrosine kinases, crizotinib has demonstrated clinical activity in MET-amplified NSCLC and ROS1-rearranged NSCLC. 5,6 Thus, crizotinib will likely play an expanding role in targeted therapy for NSCLC.Crizotinib is generally well tolerated, and most of its side effects are in the grade 1 and 2 ...

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Section: Discussioncontrasting

confidence: 50%

Heart rate decrease during crizotinib treatment and potential correlation to clinical response

Tong

Azada

et al. 2013

Cancer

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“…Recently, crizotinib was shown to decrease testosterone in male patients (36). This issue was confirmed also in a larger sample of patients.…”

Section: Crizotinib Clinical Developmentsupporting

confidence: 55%

ALK inhibitors and advanced non-small cell lung cancer (Review)

Rossi

Maione

Sacco

et al. 2014

International Journal of Oncology

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Abstract.Treatment of unselected patients with advanced non-small cell lung cancer (NSCLC) receiving third-generation platinum-based chemotherapy has reached a plateau of effectiveness. Histology and molecular analyses are the cornerstone in the initial diagnosis of NSCLC and are key determinants to address the appropriate strategy of treatment. In non-squamous histology the combination of cisplatin plus pemetrexed or carboplatin plus paclitaxel plus bevacizumab are considered today the best regimens yielding better activity and efficacy. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib, erlotinib or afatinib are the standard-of-care for patients with advanced NSCLC harbouring activating EGFR mutations. The identification of anaplastic lymphoma kinase (ALK) rearrangements in 2-5% of NSCLC patients led to the rapid clinical development of its oral TKI, crizotinib, also targeting the proto-oncogene MET and ROS1. The results reported from the first phase III trial showed superiority of crizotinib compared with standard chemotherapy in second-line treatment of ALK-positive NSCLC, which was recently approved in several countries in this setting. Unfortunately, after initial activity of crizotinib, patients will ultimately develop acquired resistances within 1 or 2 years of therapy. A second generation of ALK inhibitors, such as LDK378, alectinib and AP26113 may represent a promising treatment approach: they are under investigation with very promising early results. This review discusses ALK rearrangements, the clinical development and use of crizotinib, and other ALK-TKIs in advanced NSCLC.

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“…Recently, the University of Colorado reported that 13 men with NSCLC experienced a rapid decrease in total testosterone levels after initiating crizotinib potentially via a hypothalamic or pituitary effect, which may account for some of the fatigue experience by some patients [123]. Testosterone promptly returned to the normal level after crizotinib discontinuation.…”

Section: Endocrine Adverse Eventsmentioning

confidence: 99%

Crizotinib for the Treatment of ALK-Rearranged Non-Small Cell Lung Cancer: A Success Story to Usher in the Second Decade of Molecular Targeted Therapy in Oncology

et al. 2012

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Crizotinib, an ALK/MET/ROS1 inhibitor, was approved by the U.S. Food and Drug Administration for the treatment of anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) in August 2011, merely 4 years after the first publication of ALK-rearranged NSCLC. The crizotinib approval was accompanied by the simultaneous approval of an ALK companion diagnostic fluorescent in situ hybridization assay for the detection of ALK-rearranged NSCLC. Crizotinib continued to be developed as an ALK and MET inhibitor in other tumor types driven by alteration in ALK and MET. Crizotinib has recently been shown to be an effective ROS1 inhibitor in ROS1-rearranged NSCLC, with potential future clinical applications in ROS1-rearranged tumors. Here we summarize the heterogeneity within the ALK-and ROS1-rearranged molecular subtypes of NSCLC. We review the past and future clinical development of crizotinib for ALKrearranged NSCLC and the diagnostic assays to detect ALK-rearranged NSCLC. We highlight how the success of crizotinib has changed the paradigm of future drug development for targeted therapies by targeting a moleculardefined subtype of NSCLC despite its rarity and affected the practice of personalized medicine in oncology, emphasizing close collaboration between clinical oncologists, pathologists, and translational scientists. The Oncologist 2012; 17:1351-1375

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Rapid‐onset hypogonadism secondary to crizotinib use in men with metastatic nonsmall cell lung cancer

Cited by 88 publications

References 47 publications

Heart rate decrease during crizotinib treatment and potential correlation to clinical response

Heart rate decrease during crizotinib treatment and potential correlation to clinical response

ALK inhibitors and advanced non-small cell lung cancer (Review)

Crizotinib for the Treatment of ALK-Rearranged Non-Small Cell Lung Cancer: A Success Story to Usher in the Second Decade of Molecular Targeted Therapy in Oncology

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