Tell me about crizotinib.

Abstract
Anaplastic lymphoma kinase (ALK) gene rearrangements are present in a small subset of non-small-cell lung cancers. ALK-positivity confers sensitivity to small-molecule ALK kinase inhibitors, such as crizotinib. The integration of crizotinib into standard treatment practice in NSCLC will rest on the widespread implementation of an effective screening system for newly diagnosed patients with NSCLC which is flexible enough to incorporate new targets as treatments are developed for them. Phase I and II studies of crizotinib in ALK-positive lung cancer have demonstrated significant activity and impressive clinical benefit, which led to its early approval by USFDA in 2011. Although crizotinib induces remissions and extends the lives of patients, there have been reports of emerging resistance to Crizotinib therapy. In this review, we discuss the history, mechanism of action, uses, adverse effects, dose modifications and future challenges and opportunities for patients with ALK-positive lung cancers.

Keywords: ALK mutation, ALK inhibitors, ALK positive Non-small cell lung cancer, Crizotinib

Overview of Clinical Trials
The antitumor efficacy of crizotinib was initially demonstrated in two multicenter, single-arm studies.[23,24] Dosage for these extended series was 250 mg, orally, given twice a day, based on results from the initial phase I dose escalation study. In aggregate, these studies included 255 patients, all of whose tumors contained an ALK gene rearrangement, as shown by FISH. Overall, 95% of the patients had metastatic disease and 5% had locally advanced NSCLC. Overall, 94% of the patients had received prior systemic therapy for advanced or metastatic disease, and 76% had received two or more treatment regimens. The combined objective (complete plus partial) response rate was 55%, the majority of which was achieved during the first eight weeks of treatment. The median durations of response at the time of analysis of the two studies were 42 and 48 weeks, respectively [Table 1].

Table 1
Comparison of results of profile 1001 and profile 1005 trials

An external file that holds a picture, illustration, etc.
Object name is SAJC-2-91-g003.jpg
Evidence of the impact of crizotinib on the survival of patients came from a non-randomized, retrospective analysis of the patients enrolled in the phase I study.[25] The one- and two-year survival rates for patients treated with crizotinib were 74 and 54%, respectively, with a median follow-up of 18 months. In a cohort of 36 patients with the ALK fusion oncogene, who were not treated with crizotinib, the survival rates at one- and two-years were 44 and 12%, respectively. A comparison with a larger cohort of patients with wild-type tumors did not identify a difference when compared with those with the ALK rearrangement not treated with crizotinib, suggesting that the presence of ALK rearrangement was not prognostically significant.

Conclusions
The presence of an ALK fusion oncogene defines a molecular subset of NSCLC with distinct clinical and pathological features. The patients most likely to harbor ALK rearrangement are relatively young, never or light smokers with adenocarcinoma. Whenever possible, therapy of patients with advanced NSCLC should be individualized, based on the molecular and histological features of the tumor. If feasible, patients should have the tumor tissue assessed for the presence of a somatic mutation in the EGFR, which confers sensitivity to the EGFR tyrosine kinase inhibitors and to the ALK fusion oncogene, which is associated with sensitivity to crizotinib.

Thus, crizotinib is an important unmet medical need. It is a straightforward, biology-based biomarker, predicting a high response rate in heavily pre-treated patients and is relatively non-toxic. It is a triumph for a targeted therapy in the era of oncogenic driver mutations.
system
Tell me about crizotinib.

Abstract
Anaplastic lymphoma kinase (ALK) gene rearrangements are present in a small subset of non-small-cell lung cancers. ALK-positivity confers sensitivity to small-molecule ALK kinase inhibitors, such as crizotinib. The integration of crizotinib into standard treatment practice in NSCLC will rest on the widespread implementation of an effective screening system for newly diagnosed patients with NSCLC which is flexible enough to incorporate new targets as treatments are developed for them. Phase I and II studies of crizotinib in ALK-positive lung cancer have demonstrated significant activity and impressive clinical benefit, which led to its early approval by USFDA in 2011. Although crizotinib induces remissions and extends the lives of patients, there have been reports of emerging resistance to Crizotinib therapy. In this review, we discuss the history, mechanism of action, uses, adverse effects, dose modifications and future challenges and opportunities for patients with ALK-positive lung cancers.

Keywords: ALK mutation, ALK inhibitors, ALK positive Non-small cell lung cancer, Crizotinib

Overview of Clinical Trials
The antitumor efficacy of crizotinib was initially demonstrated in two multicenter, single-arm studies.[23,24] Dosage for these extended series was 250 mg, orally, given twice a day, based on results from the initial phase I dose escalation study. In aggregate, these studies included 255 patients, all of whose tumors contained an ALK gene rearrangement, as shown by FISH. Overall, 95% of the patients had metastatic disease and 5% had locally advanced NSCLC. Overall, 94% of the patients had received prior systemic therapy for advanced or metastatic disease, and 76% had received two or more treatment regimens. The combined objective (complete plus partial) response rate was 55%, the majority of which was achieved during the first eight weeks of treatment. The median durations of response at the time of analysis of the two studies were 42 and 48 weeks, respectively [Table 1].

Table 1
Comparison of results of profile 1001 and profile 1005 trials

An external file that holds a picture, illustration, etc.
Object name is SAJC-2-91-g003.jpg
Evidence of the impact of crizotinib on the survival of patients came from a non-randomized, retrospective analysis of the patients enrolled in the phase I study.[25] The one- and two-year survival rates for patients treated with crizotinib were 74 and 54%, respectively, with a median follow-up of 18 months. In a cohort of 36 patients with the ALK fusion oncogene, who were not treated with crizotinib, the survival rates at one- and two-years were 44 and 12%, respectively. A comparison with a larger cohort of patients with wild-type tumors did not identify a difference when compared with those with the ALK rearrangement not treated with crizotinib, suggesting that the presence of ALK rearrangement was not prognostically significant.

Conclusions
The presence of an ALK fusion oncogene defines a molecular subset of NSCLC with distinct clinical and pathological features. The patients most likely to harbor ALK rearrangement are relatively young, never or light smokers with adenocarcinoma. Whenever possible, therapy of patients with advanced NSCLC should be individualized, based on the molecular and histological features of the tumor. If feasible, patients should have the tumor tissue assessed for the presence of a somatic mutation in the EGFR, which confers sensitivity to the EGFR tyrosine kinase inhibitors and to the ALK fusion oncogene, which is associated with sensitivity to crizotinib.

Thus, crizotinib is an important unmet medical need. It is a straightforward, biology-based biomarker, predicting a high response rate in heavily pre-treated patients and is relatively non-toxic. It is a triumph for a targeted therapy in the era of oncogenic driver mutations.
user
Crizotinib is a small-molecule anaplastic lymphoma kinase (ALK) inhibitor that can be used to induce remission in non-small-cell lung cancers or NSCLC when ALK mutations are present.

In a non-randomized, retrospective analysis from a phase 1 study, crizotinib was found to improve one to two-year survival rates for patients from 44-12% to 74-54%.

Crizotinib has been shown to be a relatively non-toxic biomarker that has accomplished successful targeted therapy for people with a somatic mutation of the EGFR who have sensitivity to the ALK fusion oncogene although it remains an unmet medical need.

There have been reports of increased resistance to crizotinib which may require further research.
assistant
<|system|>
</s>
<|user|>
Tell me about crizotinib.

Abstract
Anaplastic lymphoma kinase (ALK) gene rearrangements are present in a small subset of non-small-cell lung cancers. ALK-positivity confers sensitivity to small-molecule ALK kinase inhibitors, such as crizotinib. The integration of crizotinib into standard treatment practice in NSCLC will rest on the widespread implementation of an effective screening system for newly diagnosed patients with NSCLC which is flexible enough to incorporate new targets as treatments are developed for them. Phase I and II studies of crizotinib in ALK-positive lung cancer have demonstrated significant activity and impressive clinical benefit, which led to its early approval by USFDA in 2011. Although crizotinib induces remissions and extends the lives of patients, there have been reports of emerging resistance to Crizotinib therapy. In this review, we discuss the history, mechanism of action, uses, adverse effects, dose modifications and future challenges and opportunities for patients with ALK-positive lung cancers.

Keywords: ALK mutation, ALK inhibitors, ALK positive Non-small cell lung cancer, Crizotinib

Overview of Clinical Trials
The antitumor efficacy of crizotinib was initially demonstrated in two multicenter, single-arm studies.[23,24] Dosage for these extended series was 250 mg, orally, given twice a day, based on results from the initial phase I dose escalation study. In aggregate, these studies included 255 patients, all of whose tumors contained an ALK gene rearrangement, as shown by FISH. Overall, 95% of the patients had metastatic disease and 5% had locally advanced NSCLC. Overall, 94% of the patients had received prior systemic therapy for advanced or metastatic disease, and 76% had received two or more treatment regimens. The combined objective (complete plus partial) response rate was 55%, the majority of which was achieved during the first eight weeks of treatment. The median durations of response at the time of analysis of the two studies were 42 and 48 weeks, respectively [Table 1].

Table 1
Comparison of results of profile 1001 and profile 1005 trials

An external file that holds a picture, illustration, etc.
Object name is SAJC-2-91-g003.jpg
Evidence of the impact of crizotinib on the survival of patients came from a non-randomized, retrospective analysis of the patients enrolled in the phase I study.[25] The one- and two-year survival rates for patients treated with crizotinib were 74 and 54%, respectively, with a median follow-up of 18 months. In a cohort of 36 patients with the ALK fusion oncogene, who were not treated with crizotinib, the survival rates at one- and two-years were 44 and 12%, respectively. A comparison with a larger cohort of patients with wild-type tumors did not identify a difference when compared with those with the ALK rearrangement not treated with crizotinib, suggesting that the presence of ALK rearrangement was not prognostically significant.

Conclusions
The presence of an ALK fusion oncogene defines a molecular subset of NSCLC with distinct clinical and pathological features. The patients most likely to harbor ALK rearrangement are relatively young, never or light smokers with adenocarcinoma. Whenever possible, therapy of patients with advanced NSCLC should be individualized, based on the molecular and histological features of the tumor. If feasible, patients should have the tumor tissue assessed for the presence of a somatic mutation in the EGFR, which confers sensitivity to the EGFR tyrosine kinase inhibitors and to the ALK fusion oncogene, which is associated with sensitivity to crizotinib.

Thus, crizotinib is an important unmet medical need. It is a straightforward, biology-based biomarker, predicting a high response rate in heavily pre-treated patients and is relatively non-toxic. It is a triumph for a targeted therapy in the era of oncogenic driver mutations.</s>
<|assistant|>
Crizotinib is a small-molecule anaplastic lymphoma kinase (ALK) inhibitor that can be used to induce remission in non-small-cell lung cancers or NSCLC when ALK mutations are present.

In a non-randomized, retrospective analysis from a phase 1 study, crizotinib was found to improve one to two-year survival rates for patients from 44-12% to 74-54%.

Crizotinib has been shown to be a relatively non-toxic biomarker that has accomplished successful targeted therapy for people with a somatic mutation of the EGFR who have sensitivity to the ALK fusion oncogene although it remains an unmet medical need.

There have been reports of increased resistance to crizotinib which may require further research.</s>
