Summary Basis of Decision for Vizimpro

 

Clinical Pharmacology

Dacomitinib (the medicinal ingredient in Vizimpro) is a pan-human epidermal growth factor receptor (HER) (epidermal growth factor receptor [EGFR]/HER1, HER2, and HER4) inhibitor, with clinical activity against mutated EGFR with deletions in exon 19 or the L858R substitution in exon 21. Dacomitinib is a second generation TKI that binds selectively and irreversibly to all three HER family targets thereby providing prolonged inhibition.

The clinical pharmacology data included reports on the human pharmacodynamic and pharmacokinetic studies.

Pharmacodynamics

PR Prolongation

The effect of dacomitinib on electrocardiogram (ECG) parameters was assessed using time-matched ECG which evaluated the change from baseline and corresponding pharmacokinetic data in 32 patients with advanced non-small cell lung cancer (NSCLC). Vizimpro was administered for 4 days at a supratherapeutic dose of 45 mg every 12 hours, which resulted in a mean dacomitinib peak serum concentration (C_max) value of 96.8 ng/mL, which is similar to the mean steady-state C_max reported for the therapeutic 45 mg once daily dose administered continuously to steady-state (mean C_max ranged from 79.5 to 108 ng/mL).

Dacomitinib 45 mg administered every 12 hours resulted in prolongation of the PR interval at all time points assessed on Day 4 of treatment, with a change ranging from 2.7 milliseconds (90% confidence interval [CI]: 0.5-4.9) to 6.6 milliseconds (90% CI: 4.5-8.8). No clinically meaningful effect on the QTc or the QRS complex were observed on the Day 4 assessment.

Pharmacokinetics

Dacomitinib steady state was achieved within 14 days following 45 mg QD repeated dosing and the estimated geometric mean (coefficient of variation %) accumulation ratio was 5.7 (28%) based on the area under the concentration-time curve (AUC).

Absorption

Following the administration of a single 45 mg dose of dacomitinib tablets, the mean oral bioavailability of dacomitinib is 80% compared to intravenous administration, with maximal plasma concentration occurring 5 to 6 hours (range: 2 to 24 hours) after oral dosing.

Co-administration of dacomitinib with a high fat meal increased dacomitinib exposure by 14%. However, food does not alter bioavailability to a clinically meaningful extent. Therefore, dacomitinib can be administered with or without food. However, it is recommended that dosing take place under consistent conditions (i.e., always fasted or always after the same type of meal) to avoid any unexpected increases in dacomitinib plasma concentrations.

Dacomitinib is a substrate for the membrane transport proteins P-glycoprotein (P-gp) and Breast Cancer Resistant Protein (BCRP). However, based on the oral bioavailability of 80%, efflux of dacomitinib is unlikely to have any impact on dacomitinib absorption.

Distribution

Dacomitinib is extensively distributed throughout the body with a mean steady state volume of distribution of 1,889 L following intravenous administration. In vitro binding of dacomitinib to human plasma proteins is approximately 98% and is independent of drug concentrations.

Metabolism

In humans, dacomitinib undergoes oxidation and glutathione conjugation as the major metabolic pathways. Following oral administration of a single 45 mg dose of radiolabelled dacomitinib, the most abundant circulating metabolite was O-desmethyl dacomitinib. This metabolite exhibited in vitro pharmacologic activity that was similar to that of dacomitinib in the in vitro biochemical assays. In feces, dacomitinib, O-desmethyl dacomitinib, a cysteine conjugate of dacomitinib, and a mono-oxygenated metabolite of dacomitinib were the major drug-related components. In vitro studies indicated that cytochrome P450 (CYP) 2D6 was the major CYP isozyme involved in the formation of O-desmethyl dacomitinib, while CYP3A4 contributed to the formation of other minor oxidative metabolites.

Elimination

The plasma half-life of dacomitinib ranges from 54 to 80 hours. In six healthy male subjects given a single-oral dose of radiolabelled dacomitinib, a median of 82% of the total administered radioactivity was recovered in 552 hours; feces (79% of dose) was the major route of excretion, with 3% of the dose recovered in urine.

Drug-Drug Interactions

There is the potential of drug-drug interactions with use of Vizimpro. A list of established or potential drug-drug interactions has been included in the Vizimpro Product Monograph. The drugs listed are based on either drug interaction studies, or potential interactions due to the expected magnitude and seriousness of the interaction.

Clinical Efficacy

The clinical efficacy of Vizimpro as a first-line treatment of adult patients with unresectable locally advanced or metastatic NSCLC with EGFR-activating mutations was evaluated in a pivotal Phase III Study 1050 (ARCHER 1050).

Study 1050 (ARCHER 1050)

This study was a multicentre, multinational, randomized, open-label study with the objective to demonstrate the superiority of Vizimpro compared to gefitinib in prolonging progression-free survival (PFS). Gefitinib was considered to be an acceptable comparator as it is one of the standards of care in Canada for the first-line treatment of NSCLC with EGFR-activating mutations.

A total of 452 patients were randomized 1:1 to receive Vizimpro 45 mg once daily (QD) or gefitinib 250 mg QD until disease progression or unacceptable toxicity. Stratification factors at randomization were race (Japanese vs mainland Chinese vs other East Asian vs non-East Asian) and EGFR mutation status (exon 19 deletion vs the L858R mutation in exon 21). The study was not blinded due to the differences in dose reduction strategies for the management of adverse events.

The primary efficacy endpoint was PFS as determined by a blinded Independent Radiologic Central (IRC) review based on the Response Evaluation Criteria in Solid Tumors 1.1 (RECIST v 1.1). Other efficacy endpoints included objective response rate (ORR), duration of response (DoR), and overall survival (OS). For the analysis of the primary endpoint, a gatekeeping procedure was used for hypotheses testing in a hierarchical approach to control the family-wise error rate for the analyses of primary endpoint, and key secondary endpoints of ORR and OS. The hierarchical statistical testing order was PFS followed by ORR and the OS. Crossover of patients upon disease progression was not permitted.

In the Vizimpro treatment arm, most patients were females (64.3%) with a median age of 62.0 years; 74.9% were Asian, 24.7% were White and 0.4% were Black. The majority of patients were never smokers (64.8%) and 28.6% were ex-smokers. All patients had a baseline Eastern Cooperative Oncology Group (ECOG) performance status of 0 (33.0%), or 1 (67.0%), 59.0% with exon 19 deletion, and 41.0% with L858R mutation in exon 21. Most patients had Stage IV disease (92.1%) and 7.9% had Stage IIIB; 99.1% did not receive prior systemic therapy.

Primary Efficacy Endpoint Results

Results from Study 1050, as determined by the IRC review, demonstrated a statistically significant and clinically meaningful improvement in PFS compared to gefitinib as a standard of care in the first-line setting for patients with unresectable locally advanced or metastatic EGFR-mutated NSCLC.

By the cut-off date (July 29, 2016), 59.9% of patients in the Vizimpro arm (number of patients [n] = 136) and 79.6% in the gefitinib arm (n = 179) had a PFS event. The median PFS was 14.7 months (95% CI: 11.1-16.6) for the Vizimpro arm and 9.2 months (95% CI: 9.1-11.0) for the gefitinib arm. The hazard ratio of the Vizimpro arm compared to the gefitinib arm was 0.589 (95% CI: 0.469-0.799) with a one-sided log-rank p-value <0.0001 for the stratified analysis. The hazard ratio based on the unstratified analysis was 0.582 (95% CI: 0.464-0.729) with a one-sided log-rank p-value <0.0001.

With the exception of patients older than 75 years [conclusions cannot be drawn due to the small sample size (28/227; 12.3%)], the subgroup analyses of the primary endpoint were overall consistent with the primary analysis. A cautionary statement was added to the Vizimpro Product Monograph stating that exploratory analyses did not show a benefit in efficacy endpoints for patients older than 75 years treated with Vizimpro when compared to patients aged above 75 years treated with gefitinib. With regard to the smoking status and the EGFR mutation status (at randomization and as per the Food and Drug Administration [FDA]-approved assay), the subgroup analyses for the PFS by blinded IRC review were generally in favour of the Vizimpro treatment group rather than the gefitinib treatment group.

For the non-Asian subgroup, there was no clinically significant difference in the median PFS between the Vizimpro treatment group (9.3 months; 95% CI: 5.5-12.8) and the gefitinib treatment group (9.2 months; 95% CI: 7.4-11.1). The hazard ratio, although below 1, was not statistically significant. The inconclusive results could be attributable to the small size and the large confidence intervals. The proportions of non-Asian patients who were responders (with a complete response or partial response) were similar between the two study arms (68.4% for the Vizimpro arm vs 67.3% for the gefitinib arm). The proportions of non-responders in the non-Asian subgroup were also similar between the Vizimpro arm (31.6%) and the gefitinib arm (32.7%). The duration of response for the non-Asian subgroup was greater in the Vizimpro arm (10.1 months; 95% CI: 6.8-13.8) than the gefitinib arm (6.6 months; 95% CI: 5.2-30.4). The hazard ratio for PFS was 0.547 (95% CI: 0.321-0.933) in non-Asian responders and 2.498 (95% CI: 1.004-6.213) in non-Asian non-responders. Taken together, these results still suggest a gain in efficacy in non-Asian patients.

Key Secondary Efficacy Endpoints

There were no differences in the ORR between the two treatment arms (74.9% for the Vizimpro group and 71.6% for the gefitinib arm), with a one-sided p-value of 0.1942. A total of 5.3% of the responses achieved in Vizimpro-treated patients were complete responses, whereas 1.8% of the patients treated with gefitinib achieved complete response. Given that ORR was not statistically significant, the statistical testing procedures were not carried further. The median duration of response was longer for Vizimpro-treated patients (14.8 months; 95% CI: 12.0-17.4) compared to gefitinib-treated patients (8.3 months; 95% CI: 7.4-9.2).

The final analysis for OS stratified by race and EGFR mutation status was conducted at the cut-off date of February 17, 2017 when the prespecified number of events was met. A total of 220 deaths (48.7%) occurred, with 103 deaths (45.4%) in the Vizimpro arm and 117 deaths (52.0%) in the intent-to-treat (ITT) population. Although the Kaplan-Meier curves crossed twice, the proportional hazard assumption was maintained. The median OS was 34.1 months (95% CI: 29.5-37.7) in Vizimpro-treated patients and 26.8 months (95% CI: 23.7-32.1) in gefitinib-treated patients. The stratified hazard ratio was 0.760 (95% CI: 0.582-0.993) with a stratified log-rank test one-sided p-values of 0.0219. The median follow-up for OS was 31.1 months in the ITT population. Although the log-rank test p-value for the HR was below 0.05, the observed gain in OS is not considered to be statistically significant due to the gate-keeping procedure stopped at the testing of independently assessed ORR as the ORR was not statistically significant. This p-value is therefore considered nominal and no statistical significance can be claimed. The results for OS are therefore descriptive and the p-values for OS are not included in the Vizimpro Product Monograph.

Indication

The New Drug Submission for Vizimpro was filed by the sponsor with the following indication:

• Vizimpro (dacomitinib) is indicated as first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR)-activating mutations. The prespecified final analysis of overall survival (OS) demonstrated that dacomitinib resulted in a significant and clinically meaningful improvement in OS vs gefitinib.

Health Canada approved the following indication:

• Vizimpro (dacomitinib) is indicated as first-line treatment of adult patients with unresectable locally advanced or metastatic non-small cell lung cancer (NSCLC) with confirmed epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations.

For more information, refer to the Vizimpro Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Safety

The clinical safety for Vizimpro was primarily evaluated in Study 1050 (ARCHER 1050) described in the Clinical Efficacy section. In Study 1050, 227 patients received Vizimpro 45 mg QD and 224 patients received the comparator gefitinib 250 mg QD. The safety endpoint was the overall safety profile, including adverse events and laboratory abnormalities. Additional safety assessments included concomitant medications used, vital signs, body weight, ECOG performance status, left ventricular ejection fraction, and ECGs.

Overall Exposure

The median duration of exposure in Study 1050 was 14.5 weeks longer for patients who were treated with Vizimpro (66 weeks; range 0.3 to 162.7 weeks) compared to gefitinib (52.1 weeks; range: 0.3 to 148.3 weeks). Vizimpro-treated patients received more treatment cycles than gefitinib-treated patients (median of 17.0 vs 13.0). The median dose intensity was lower for the Vizimpro group compared to the gefitinib arm (72.5% vs 99.8%). The safety analyses were not adjusted for the longer duration of treatment in Vizimpro-treated patients.

Treatment Modifications

Based on the incidence of treatment modifications, Vizimpro was less tolerable than gefitinib. The incidence of adverse events requiring dose reductions was 8-fold greater in the Vizimpro arm than the gefitinib arm (66.1% vs 8.0%). There were more patients in the Vizimpro arm that required interruptions to manage adverse events (57.3% vs 26.8%). More patients permanently discontinued treatment due to treatment-emergent adverse events (TEAEs) in the Vizimpro arm than in the gefitinib arm (17.6% vs 12.1%). The most frequent TEAEs (≥1%) leading to Vizimpro discontinuation were disease progression (2.6%), pneumonia (2.2%), and dermatitis acneiform (1.3%).

Adverse Events Overview

The majority of patients in both study arms experienced TEAEs (Vizimpro arm: 99.6% vs gefitinib arm: 98.2%). The system organ class for which TEAEs were most frequently observed in Vizimpro-treated patients were gastrointestinal disorders (93.4%), skin and subcutaneous tissue disorders (91.6%), infections and infestations (79.3%), investigations (59.0%), respiratory, thoracic, and mediastinal disorders (54.6%), general disorders and administration site conditions (52.0%), metabolism and nutrition disorders (46.7%), musculoskeletal pain (37.0%), and psychiatric disorders (14.5%).

Treatment-emergent adverse events that were reported in more than 10% of Vizimpro-treated patients were diarrhea (87.2%), paronychia (61.7%), dermatitis acneiform (48.9%), stomatitis (43.6%), decreased appetite (30.8%), dry skin (27.8%), weight decreased (25.6%), alopecia (23.2%), cough (21.1%), pruritus (19.8%), increased alanine aminotransferase (ALT; 19.4%), nausea (18.9%), conjunctivitis (18.9%), increased aspartate aminotransferase (AST; 18.5%), rash (17.6%), palmar-plantar erythrodysesthesia syndrome (PPES; 14.5%), pain in extremity (13.7%), dyspnea (13.2%), constipation (12.8%), asthenia (12.8%), mouth ulceration (12.3%), maculo-papular rash (12.3%), upper respiratory tract infection (12.3%), musculoskeletal pain (11.5%), dermatitis (11.0%), and insomnia (10.6%).

Grade 3 or 4 Adverse Events

Patients treated with Vizimpro experienced a higher incidence of greater than Grade 3 TEAEs than patients treated with gefitinib (61.6% vs 38.8%), most of these being Grade 3 in severity for both study groups (51.1% for Vizimpro and 29.9% for gefitinib). The majority of the Grade 3 TEAEs were considered treatment-related (47.1% vs 29.9% for gefitinib). Grade 3 events reported in Vizimpro-treated patients included dermatitis acneiform (13.7%), diarrhea (8.4%), paronychia (7.5%), rash (4.4%), maculo-papular rash (4.4%), hypokalemia (4.0%), pustular rash (3.5%), stomatitis (3.5%), decreased appetite (3.1%), asthenia (2.2%), decreased lymphocyte count (2.2 %), pleural effusion (2.2%), decreased weight (2.2), increased ALT (0.9%), and anemia (0.9%). The Grade 3 TEAEs of increased ALT (8.5%), anemia (2.2%), and increased AST (4.0%) occurred more frequently in gefitinib-treated patients.

Grade 5 Adverse Events

Deaths that occurred within 28 days of the last dose administered were reported as fatal TEAEs. In both study arms, most deaths occurred more than 28 days after the last dose administration. The incidences of death within 28 days of the last dose administration were similar between both groups (9.3% for Vizimpro and 8.5% for gefitinib). Fewer deaths from all causes occurred in the Vizimpro arm than in the gefitinib arm more than 28 days after the last dose administration (24.2% vs 32.1%).

Grade 5 TEAEs occurred in 9.7% of patients in the Vizimpro arm and in 8.9% of patients in the gefitinib arm. Treatment-emergent adverse events leading to death in the Vizimpro arm were disease progression, pneumonia, diarrhea, and respiratory failure.

Laboratory Abnormalities

In the Vizimpro arm, shifts to Grade 3 were observed for hypokalemia (5.7%), hypermagnesemia (3.1%), hyponatremia (2.6%), increased ALT (1.3%), hypocalcemia (1.3%), increased alkaline phosphatase (0.9%), hyperglycemia (0.9%), hypomagnesemia (0.9%), increased AST (0.4%), increased bilirubin (0. 4%), and hypercalcemia (0.4%).

Shifts to Grade 4 adverse events were reported for hypoglycemia (0.4%), hypokalemia (0.9%), and hyponatremia (0.4%).