Zykadia

Pharmacotherapeutic group: antineoplasic and immunomodulating agents, ATC code: L01XE28. Mechanism of action Ceritinib is an orally highly selective and potent ALK inhibitor. Ceritinib inhibits autophosphorylation of ALK, ALK-mediated phosphorylation of downstream signalling proteins and proliferation of ALK-dependent cancer cells both in vitro and in vivo . ALK translocation determines expression of the resulting fusion protein and consequent aberrant ALK signaling in NSCLC. In the majority of NSCLC cases, EML4 is the translocation partner for ALK; this generates an EML4-ALK fusion protein containing the protein kinase domain of ALK fused to the N-terminal part of EML4. Ceritinib was demonstrated to be effective against EML4-ALK activity in a NSCLC cell line (H2228), resulting in inhibition of cell proliferation in vitro and regression of tumours in H2228-derived xenografts in mouse and rat. Clinical efficacy and safety Previously untreated ALK-positive advanced NSCLC - randomised phase 3 Study A2301 (ASCEND-4) The efficacy and safety of Zykadia for the treatment of advanced ALK-positive NSCLC patients who have not received previous systemic treatment anti-cancer therapy (including ALK inhibitor) with the exception of neo-adjuvant or adjuvant therapy, was demonstrated in a global multicentre, randomised, open-label phase 3 Study A2301. A total of 376 patients were randomised in a 1:1 ratio (stratified by WHO performance status, prior adjuvant/neoadjuvant chemotherapy and presence/absence of brain metastasis at screening) to receive either ceritinib (750 mg daily, fasted) or chemotherapy (based on investigator's choice - pemetrexed [500 mg/m 2 ] plus cisplatin [75 mg/m 2 ] or carboplatin [AUC 5-6], administered every 21 days). Patients who completed 4 cycles of chemotherapy (induction) without progressive disease subsequently received pemetrexed (500 mg/m 2 ) as single-agent maintenance therapy every 21 days. One hundred and eighty-nine (189) patients were randomised to ceritinib and one hundred eighty-seven (187) were randomised to chemotherapy. The median age was 54 years (range: 22 to 81 years); 78.5% of patients were younger than 65 years. A total of 57.4% of patients were female. 53.7% of the study population was Caucasian, 42.0% Asian, 1.6% Black and 2.6% other races The majority of patients had adenocarcinoma (96.5%) and had either never smoked or were former smokers (92.0%). The Eastern Cooperative Oncology Group (ECOG) performance status was 0/1/2 in 37.0%/56.4%/6.4% of patients, and 32.2% had brain metastasis at baseline. 59.5% of patients with brain metastasis at baseline received no prior radiotherapy to the brain. Patients with symptomatic CNS (central nervous system) metastases who were neurologically unstable or had required increasing doses of steroids within the 2 weeks prior to screening to manage CNS symptoms, were excluded from the study. Patients were allowed to continue the assigned study treatment beyond initial progression in case of continued clinical benefit as per the investigator's opinion. Patients randomised to the chemotherapy arm could cross-over to receive ceritinib upon RECIST-defined disease progression confirmed by blinded independent review committee (BIRC). One hundred and five (105) patients out of the 145 patients (72.4%) that discontinued treatment in the chemotherapy arm received subsequent ALK inhibitor as first antineoplastic therapy. Of these patients 81 received ceritinib. The median duration of follow-up was 19.7 months (from randomisation to cut-off date). The study met its primary objective demonstrating a statistically significant improvement in progression free survival (PFS) by BIRC (see Table 3 and Figure 1). The PFS benefit of ceritinib was consistent by investigator assessment and across various subgroups including age, gender, race, smoking class, ECOG performance status and disease burden. The overall survival (OS) data was not mature with 107 deaths representing approximately 42.3% of the required events for the final OS analysis. Efficacy data from Study A2301 are summarised in Table 3, and the Kaplan-Meier curves for PFS and OS are shown in Figure 1 and Figure 2, respectively. Table 3 ASCEND-4 (Study A2301) - Efficacy results in patients with previously untreated ALK-positive advanced NSCLC Ceritinib (N=189) Chemotherapy (N=187) Progression-free survival (based on BIRC) Number of events, n (%) 89 (47.1) 113 (60.4) Median, months d (95% CI) 16.6 (12.6, 27.2) 8.1 (5.8, 11.1) HR (95% CI) a 0.55 (0.42, 0.73) p-value b <0.001 Overall survival c Number of events, n (%) 48 (25.4) 59 (31.6) Median, months d (95% CI) NE (29.3, NE) 26.2 (22.8, NE) OS rate at 24 months d , % (95% CI) 70.6 (62.2, 77.5) 58.2 (47.6, 67.5) HR (95% CI) a 0.73 (0.50,1.08) p-value b 0.056 Tumour response (based on BIRC) Overall response rate (95% CI) 72.5% (65.5, 78.7) 26.7% (20.5, 33.7) Duration of response (based on BIRC) Number of responders 137 50 Median, months d (95% CI) 23.9 (16.6, NE) 11.1 (7.8, 16.4) Event-free rate at 18 months d , % (95% CI) 59.0 (49.3, 67.4) 30.4 (14.1, 48.6) HR=hazard ratio; CI=confidence interval; BIRC=Blinded Independent Review Committee; NE=not estimable a Based on the Cox proportional hazards stratified analysis. b Based on the stratified log-rank test. c OS analysis was not adjusted for the effects of cross-over. d Estimated using the Kaplan-Meier method. Figure 1 ASCEND-4 (Study A2301) - Kaplan-Meier curves of progression-free survival as assessed by BIRC Figure 2 ASCEND-4 (Study A2301)- Kaplan-Meier plot of overall survival by treatment arm Patient reported outcome questionnaires (Lung cancer symptom scale [LCSS], EORTC-QLQ-C30 [C30], EORTC QLQ-LC13 [LC13] and EQ-5D-5L) were completed by 80% or more of patients in the ceritinib and chemotherapy arms for all questionnaires at most of the time-points during the course of the study. Ceritinib significantly prolonged time to deterioration for the pre-specified lung cancer specific symptoms of interest of cough, pain and dyspnoea (composite endpoint LCSS: HR=0.61, 95% CI: 0.41, 0.90, median Time to Deterioration [TTD] NE [95% CI: 20.9, NE] in the ceritinib arm versus 18.4 months [13.9, NE] in the chemotherapy arm; LC13: HR=0.48, 95% CI: 0.34, 0.69, median TTD 23.6 months [95% CI: 20.7, NE] in the ceritinib arm versus 12.6 months [95% CI: 8.9, 14.9] in the chemotherapy arm). Patients receiving ceritinib showed significant improvements over chemotherapy in general Quality of Life and global Health Status measures (LCSS [p<0.001], QLQ-C30, [p<0.001] and EQ-5D-5L index [p<0.001]). In Study A2301, 44 patients with measurable brain metastasis at baseline and at least one post-baseline brain radiological assessment (22 patients in the ceritinib arm and 22 patients in the chemotherapy arm) were assessed for intracranial response by BIRC neuro-radiologist per modified RECIST 1.1 (i.e. up to 5 lesions in the brain). The overall intracranial response rate (OIRR) was higher with ceritinib (72.7%, 95% CI: 49.8, 89.3) as compared to the chemotherapy arm (27.3%, 95% CI: 10.7, 50.2). The median PFS by BIRC using RECIST 1.1 was longer in the ceritinib arm compared to the chemotherapy arm in both subgroups of patients with brain metastases and without brain metastases. The median PFS in patients with brain metastases was 10.7 months (95% CI: 8.1, 16.4) versus 6.7 months (95% CI: 4.1, 10.6) in the ceritinib and chemotherapy arms, respectively, with HR=0.70 (95% CI: 0.44, 1.12). The median PFS in patients without brain metastases was 26.3 months (95% CI: 15.4, 27.7) versus 8.3 months (95% CI: 6.0, 13.7) in the ceritinib and chemotherapy arms, respectively, with HR=0.48 (95% CI: 0.33, 0.69). Previously treated ALK-positive advanced NSCLC - randomised phase 3 Study A2303 (ASCEND-5) The efficacy and safety of Zykadia for the treatment of ALK-positive advanced NSCLC patients who have received previous treatment with crizotinib, was demonstrated in a global multicentre, randomised, open-label phase 3 Study A2303. A total of 231 patients with advanced ALK positive NSCLC who have received prior treatment with crizotinib and chemotherapy (one or two regimen including a platinum-based doublet) were included in the analysis. One hundred fifteen (115) patients were randomised to Zykadia and one hundred sixteen (116) were randomised to chemotherapy (either pemetrexed or docetaxel). Seventy-three (73) patients received docetaxel and 40 received pemetrexed. In the ceritinib arm, 115 patients were treated with 750 mg once daily fasted. The median age was 54.0 years (range: 28 to 84 years); 77.1% of patients were younger than 65 years. A total of 55.8% of patients were female. 64.5% of the study population were Caucasian, 29.4% Asian, 0.4% Black and 2.6% other races. The majority of patients had adenocarcinoma (97.0%) and had either never smoked or were former smokers (96.1%). The ECOG performance status was 0/1/2 in 46.3%/47.6%/6.1% of patients respectively, and 58.0% had brain metastasis at baseline. All patients were treated with prior crizotinib. All except one patient received prior chemotherapy (including a platinum doublet) for advanced disease; 11.3% of the patients in the ceritinib arm and 12.1% of the patients in the chemotherapy arm were treated with two prior chemotherapy regimen for advanced disease. Patients were allowed to continue the assigned study treatment beyond initial progression in case of continued clinical benefit as per the investigator's opinion. Patients randomised to the chemotherapy arm could further crossover to receive Zykadia upon RECIST-defined disease progression confirmed by BIRC. The median duration of follow-up was 16.5 months (from randomisation to data cut-off date). The study met its primary objective demonstrating a statistically significant improvement in PFS by BIRC with an estimated 51% risk reduction in the ceritinib arm compared to chemotherapy arm (see Table 4 and Figure 3). The PFS benefit of Zykadia was consistent across various subgroups including age, gender, race, smoking class, ECOG performance status, and presence of brain metastases or prior response to crizotinib. The PFS benefit was further supported by local investigator assessment, and analysis of overall response rate (ORR) and disease control rate (DCR). OS data was immature with 48 (41.7%) events in the ceritinib arm and 50 (43.1%) events in the chemotherapy arm, corresponding to approximately 50% of the required events for the final OS analysis. In addition, 81 patients (69.8%) in the chemotherapy arm received subsequent Zykadia as first antineoplastic therapy after study treatment discontinuation. Efficacy data from Study A2303 are summarised in Table 4, and the Kaplan-Meier curves for PFS and OS are shown in Figure 3 and 4, respectively. Table 4 ASCEND-5 (Study A2303) – Efficacy results in patients with previously treated ALK-positive metastatic/advanced NSCLC Ceritinib (N=115) Chemotherapy (N=116) Duration of follow-up Median (months) (min – max) 16.5 (2.8 – 30.9) Progression-free survival (based on BIRC) Number of events, n (%) 83 (72.2%) 89 (76.7%) Median, months (95% CI) 5.4 (4.1, 6.9) 1.6 (1.4, 2.8) HR (95% CI) a 0.49 (0.36, 0.67) p-value b <0.001 Overall survival c Number of events, n (%) 48 (41.7%) 50 (43.1%) Median, months (95% CI) 18.1 (13.4, 23.9) 20.1 (11.9, 25.1) HR (95% CI) a 1.00 (0.67,1.49) p-value b 0.496 Tumour responses (based on BIRC) Objective response rate (95% CI) 39.1% (30.2, 48.7) 6.9% (3.0, 13.1) Duration of response Number of responders 45 8 Median, months d (95% CI) 6.9 (5.4, 8.9) 8.3 (3.5, NE) Event-free probability estimate at 9 months d (95% CI) 31.5% (16.7%, 47.3%) 45.7% (6.9%, 79.5%) HR=hazard ratio; CI=confidence interval; BIRC=Blinded Independent Review Committee; NE=not estimable a Based on the stratified Cox proportional hazards analysis. b Based on the stratified log-rank test. c OS analysis was not adjusted for the potentially confounding effects of cross over. d Estimated using the Kaplan-Meier method. Figure 3 ASCEND-5 (Study A2303) – Kaplan-Meier plot of progression-free survival as assessed by BIRC Figure 4 ASCEND-5 (Study A2303) – Kaplan-Meier plot of overall survival by treatment arm Patient reported outcome questionnaires were collected using the EORTC QLQ C30/LC13, LCSS and EQ-5D-5L. 75% or more of patients in the ceritinib and chemotherapy arms completed the LCSS questionnaires at most of the time points during the course of the study. Significant improvements were reported for the majority of lung cancer specific symptoms for Zykadia compared to chemotherapy (four out of six LCSS and 10 out of 12 QLQ-LC13 symptom scores). Ceritinib significantly prolonged time to deterioration for the lung cancer specific symptoms of interest of cough, pain and dyspnoea (composite endpoint LCSS: HR=0.40; 95% CI: 0.25, 0.65, median Time to Deterioration [TTD] 18.0 months [95% CI: 13.4, NE] in the ceritinib arm versus 4.4 months [95% CI: 1.6, 8.6] in the chemotherapy arm; LC13: HR=0.34; 95% CI: 0.22, 0. 52, median TTD 11.1 months [95% CI: 7.1, 14.2] in the ceritinib arm versus 2.1 months [95% CI: 1.0, 5.6] in the chemotherapy arm). The EQ-5D questionnaire showed a significant overall health status improvement for Zykadia in comparison to the chemotherapy. In Study A2303, 133 patients with baseline brain metastasis (66 patients in the Zykadia arm and 67 patients in the chemotherapy arm) were assessed for intracranial response by BIRC neuro-radiologist (per modified RECIST 1.1 (i.e. up to 5 lesions in the brain). The OIRR in patients with measurable disease in the brain at baseline and at least one post-baseline assessment was higher in the ceritinib arm (35.3%, 95% CI: 14.2, 61.7) compared to the chemotherapy arm (5.0%, 95% CI: 0.1, 24.9). The median PFS by BIRC using RECIST 1.1 was longer in the ceritinib arm compared to the chemotherapy arm in both subgroups of patients with brain metastases and without brain metastases. The median PFS in patients with brain metastases was 4.4 months (95% CI: 3.4, 6.2) versus 1.5 months (95% CI: 1.3, 1.8) in the ceritinib and chemotherapy arms, respectively with HR=0.54 (95% CI: 0.36, 0.80). The median PFS in patients without brain metastases was 8.3 months (95% CI: 4.1, 14.0) versus 2.8 months (95% CI: 1.4, 4.1) in the ceritinib and chemotherapy arms, respectively with HR=0.41 (95% CI: 0.24, 0.69). Dose optimisation Study A2112 (ASCEND-8) The efficacy of Zykadia 450 mg with food was evaluated in a multicentre, open-label dose optimisation study A2112 (ASCEND-8). A total of 147 previously untreated patients with ALK-positive locally advanced or metastatic NSCLC were randomised to receive Zykadia 450 mg once daily with food (N=73) or Zykadia 750 mg once daily under fasted conditions (N=74). A key secondary efficacy endpoint was ORR according to RECIST 1.1 as evaluated by BIRC. The population characteristics of the previously untreated patients with ALK-positive locally advanced or metastatic NSCLC across the two arms, 450 mg with food (N=73) and 750 mg fasted (N=74), were: mean age 54.3 and 51.3 years, age less than 65 (78.1% and 83.8%), female (56.2% and 47.3%), Caucasian (49.3% and 54.1%), Asian (39.7% and 35.1%), never or former smoker (90.4% and 95.9%), WHO PS 0 or 1 (91.7% and 91.9%), adenocarcinoma histology (98.6% and 93.2%), and metastases to the brain (32.9% and 28.4%), respectively. Efficacy results from ASCEND-8 are summarised in Table 5 below. Table 5 ASCEND-8 (Study A2112) - Efficacy results in patients with previously untreated ALK-positive locally advanced or metastatic NSCLC by BIRC Efficacy Parameter Ceritinib 450 mg with food (N=73) Ceritinib 750 mg fasted (N=74) Overall Response Rate (ORR: CR+PR), n (%) (95% CI) a 57 (78.1) (66.9, 86.9) 56 (75.7) (64.3, 84.9) CI: Confidence Interval Complete Response (CR), Partial Response (PR) confirmed by repeat assessments performed not less than 4 weeks after response criteria were first met Overall response rate determined based on BIRC assessment per RECIST 1.1 a Exact binomial 95% confidence interval Single arm studies X2101 and A2201 The use of Zykadia in the treatment of ALK-positive NSCLC patients previously treated with an ALK inhibitor was investigated in two global, multicentre, open-label, single-arm phase 1/2 studies (Study X2101 and Study A2201). In study X2101 a total of 246 ALK-positive NSCLC patients were treated at a Zykadia dose of 750 mg once daily fasted: 163 who had received prior treatment with an ALK inhibitor and 83 who were ALK inhibitor naïve. Of the 163 ALK-positive NSCLC patients who had received prior treatment with an ALK inhibitor, the median age was 52 years (range: 24-80 years); 86.5% were younger than 65 years and 54% were female. The majority of patients were Caucasian (66.3%) or Asian (28.8%). 93.3% had adenocarcinoma and 96.9% had either never been or were former smokers. All of the patients were treated with at least one regimen prior to enrolment into the study and 84.0% with two or more regimens. Study A2201 involved 140 patients who had been previously treated with 1-3 lines of cytotoxic chemotherapy followed by treatment with crizotinib, and who had then progressed on crizotinib. The median age was 51 years (range: 29-80 years); 87.1% of patients were younger than 65 years and 50.0% were female. The majority of patients were Caucasian (60.0%) or Asian (37.9%). 92.1% of patients had adenocarcinoma. The main efficacy data for both studies are summarised in Table 6. Final overall survival (OS) data are presented for Study A2201. For Study X2101, OS data were not yet mature at the time of the analysis. Table 6 ALK-positive advanced NSCLC - overview of efficacy results from Studies X2101 and A2201 Study X2101 ceritinib 750 mg Study A2201 ceritinib 750 mg N=163 N=140 Duration of follow-up Median (months) (min – max) 10.2 (0.1 – 24.1) 14.1 (0.1 – 35.5) Overall response rate Investigator (95% CI) 56.4% (48.5, 64.2) 40.7% (32.5, 49.3) BIRC (95% CI) 46.0% (38.2, 54.0) 35.7% (27.8, 44.2) Duration of response* Investigator (months, 95% CI) 8.3 (6.8, 9.7) 10.6 (7.4, 14.7) BIRC (months, 95% CI) 8.8 (6.0, 13.1) 12.9 (9.3, 18.4) Progression-free survival Investigator (months, 95% CI) 6.9 (5.6, 8.7) 5.8 (5.4, 7.6) BIRC (months, 95% CI) 7.0 (5.7, 8.7) 7.4 (5.6, 10.9) Overall survival (months, 95% CI) 16.7 (14.8, NE) 15.6 (13.6, 24.2) NE = not estimable Study X2101: Responses assessed using RECIST 1.0 Study A2201: Responses assessed using RECIST 1.1 *Includes only patients with confirmed CR, PR In Studies X2101 and A2201, brain metastases were seen in 60.1% and 71.4% of patients, respectively. The ORR, DOR and PFS (by BIRC assessment) for patients with brain metastases at baseline were in line with those reported for the overall population of these studies. Non-adenocarcinoma histology Limited information is available in ALK-positive NSCLC patients with non-adenocarcinoma histology. Elderly Limited efficacy data are available in elderly patients. No efficacy data are available in patients over 85 years of age. Paediatric population The European Medicines Agency has waived the obligation to submit the results of studies with Zykadia in all subsets of the paediatric population in lung carcinoma (small cell and non-small cell carcinoma) (see section 4.2 for information on paediatric use).