Second line setting - ALK-positiver
The evidence supporting this protocol is provided by a phase III open label multicentre international randomised trial, involving 347 patients with locally advanced or metastatic ALK-positive non small cell lung cancer, who had previously received a platinum based regimen, comparing crizotinib with intravenous chemotherapy, either pemetrexed or docetaxel.r
Between February 2010 and February 2012, 173 patients were randomised to receive oral treatment with crizotinib (250 mg twice daily) and 174 patients were randomised to receive intravenous chemotherapy. 99 patients in the chemotherapy group received pemetrexed (500 mg/m2), and 72 received docetaxel (75 mg/m2) every three weeks.
The primary end point was progression free survival (PFS), and secondary end points included overall survival (OS), response rate (RR), safety and patient-reported outcomes.
First line setting - ALK-positiver
The evidence supporting the use of crizotinib in the first line setting is provided by a phase III open label multicentre randomised trial, involving 343 treatment naive patients with advanced ALK-positive, non-squamous, non small cell lung cancer, comparing crizotinib with intravenous chemotherapy (pemetrexed plus cisplatin or carboplatin).
Between January 2011 and July 2013, 343 chemotherapy naive patients with advanced non-squamous ALK-positive NSCLC were randomised 1:1 to receive either crizotinib (250 mg) twice daily, or pemetrexed (500 mg/m2) plus either cisplatin (75 mg/m2) or carboplatin (AUC 5-6), intravenously every 21 days for up to six cycles. In the chemotherapy group, crossover to crizotinib was permitted after disease progression.
The primary end point was progression free survival as assessed by independent radiologic review, and secondary end points included overall survival, objective response rate, safety and patient reported outcomes.
ROS1-positiver
The evidence supporting the use of crizotinib in patients with ROS1-positive disease is provided by a phase II open label multicentre single-arm trial in East Asian patients with advanced non-squamous ROS1-positive non small cell lung cancer.
Between September 2013 and January 2015, 127 East Asian patients (24 chemotherapy naïve, 103 pretreated with 2 median prior lines of therapy) with advanced non-squamous ROS1-positive non small cell lung cancer were commenced on treatment with crizotinib (250 mg) twice daily. The primary end point was objective response rate as assessed by independent radiologic review, and secondary end points included duration of response, time to first tumour response, disease control rate, progression-free survival, and overall survival. Safety and patient-reported outcomes were also assessed.
Efficacy
Second line setting - ALK-positiver
At the time of data cut off in March 2012, the median PFS was 7.7 months in the crizotinib group vs 3.0 months in the chemotherapy group (HR= 0.49; 95% CI 0.37-0.64; P<0.001). An interim analysis showed no overall survival advantage, however, this data was immature at the time of reporting, and likely to be confounded by a high crossover rate among patients in the chemotherapy group.
Kaplan-Meier curve for Overall Survival (intention-to-treat population)r
© New Engl J Med 2013
First line setting - ALK positiver
Progression-free survival was significantly longer in patients assigned to receive crizotinib, compared to those who received chemotherapy (median 10.9 versus 7 months; HR 0.454; 95% CI 0.35-0.60). There was no significant difference found in overall survival (HR 0.82, 95% CI 0.54-1.26), however, 70% of patients initially randomised to receive chemotherapy crossed over and were subsequently treated with crizotinib. Furthermore, there was a low rate of death from any cause (26%) in the entire study population, which also contributed to this finding.
Kaplan-Meier curve for Progression Free and Overall Survivalr
© N Engl J Med 2014
Response rate
In the intention-to-treat population for patients with ALK-positive disease in the further line setting, the response rate was 65% (95%CI 58-72) in the crizotinib group, compared with 20% (95% CI 21-39) in the chemotherapy group (p=0.001). In the as-treated population, response rates for crizotinib remained significantly higher than with either type of chemotherapy.r
The objective response rate was also significantly increased in patients receiving crizotinib in the first line setting, compared to those receiving first line chemotherapy (74% vs 45%; p=0.0001).r
© New Engl J Med 2014
Patient-reported outcomes
In the second line setting there was a significantly greater overall reduction from baseline in a variety of symptoms with crizotinib than with chemotherapy (see table below). The median time to deterioration of a composite end point of three symptoms was significantly longer with crizotinib: 5.6 months versus 1.4 months with chemotherapy (HR with crizotinib, 0.54; 95% CI, 0.40-0.71; p<0.001). Additionally, there was a significantly greater overall improvement from baseline in global quality of life in the crizotinib group (see table below).r
© New Engl J Med 2013
First line setting
In the first line setting, crizotinib was similarly associated with a greater patient-reported improvement in quality of life and a reduction in lung cancer symptoms.r
© New Engl J Med 2014
ROS1-positive
Progression-free survival (PFS) was 15.9 months (95% CI 13-24) and overall survival (OS) was 32.5 months (95% CI 32-NR) in this single-arm study. The response rate was 71.7% (95% CI 63-79%). There were no new safety signals identified in this patient population compared to previous trials using crizotinib.r
Toxicity
Second line settingr
The most common adverse events with crizotinib were vision disorder, diarrhoea, nausea, vomiting, constipation, elevated liver aminotransferase levels, oedema, upper respiratory infection, dysgeusia and dizziness. The majority of these events were mild (Grade 1 or 2), with the exception of elevated aminotransferase levels (Grade 3 or 4).
Grade 3 or 4 events occurred with similar incidence in both the crizotinib and chemotherapy groups (33% and 32% respectively). Treatment related serious adverse events were also similar (12% for crizotinib, 14 for chemotherapy). Permanent discontinuation secondary to adverse events occurred in 6% of those receiving crizotinib, and 10% of those receiving chemotherapy.
In those receiving crizotinib, 13% developed Grade 3 or 4 neutropenia, including one incident of febrile neutropenia. In the chemotherapy group, 19% developed Grade 3 or 4 neutropenia, with 16 cases of febrile neutropenia.
Three treatment-related deaths occurred in the crizotinib group: one attributed to ventricular arrhythmia, and two to interstitial lung disease or pneumonitis. Hepatic dysfunction developed in one patient, who died of hepatic failure after the data cut off date.
© New Engl J Med 2013
First line settingr
The most common adverse effects associated with crizotinib therapy were visual disorder (71% of patients), diarrhoea (61%) and oedema (49%). The relative incidence of fatigue, anaemia and neutropenia was significantly greater in the chemotherapy group.
Most adverse events in both groups were grade 1 or 2 in severity. Grade 3 or 4 elevations in ALT levels occurred in 11% of patients receiving crizotinib, and 2% of those in the chemotherapy group. these elevations were primarily managed by way of dose interruptions or reductions. No deaths from hepatic dysfunction occurred, however four patients were permanently discontinued from crizotinib therapy following hepatic events.
Grade 3 or 4 neutropenia occurred in 11% of patients receiving crizotinib, and in 15% of those receiving chemotherapy. no events of febrile neutropenia occurred in the crizotinib group with two cases in the chemotherapy group.
There was one treatment-related cause of death- fatal pneumonitis - attributed to crizotinib. A further two patients in the crizotinib group had their treatment permanently discontinued due to pneumonitis.