Summary Basis of Decision for Portrazza

 

Clinical Pharmacology

Necitumumab, the medicinal ingredient of Portrazza, is a recombinant human immunoglobulin G1 monoclonal antibody that binds with high affinity and specificity to the human epidermal growth factor receptor (EGFR) and blocks the ligand binding site, blocking activation by all known ligands and inhibiting relevant biological effects in vitro. Studies demonstrate that Portrazza inhibits EGFR-dependent tumour cell proliferation, and can exert cytotoxic effect in tumour cells through antibody-dependent cell-mediated cytotoxicity.

The appropriate clinical dosage regimen was sought on the basis of safety and pharmacokinetic (PK) data from two Phase I dose-escalation studies. However, a non-validated bioanalytical method was used in the measurement of necitumumab concentrations, and the maximum tolerated dose was based on very limited safety data. Other studies, using the validated bioanalytical method, evaluated alternative dosing schedules. Population pharmacokinetic/pharmacodynamic modelling (including data from the Phase III studies SQUIRE and INSPIRE) supported that the selected clinical dose regimen of 800 mg given on days 1 and 8 of each 3-week cycle is the appropriate dose and regimen in terms of minimizing toxicity while maintaining efficacy.

After an initial peak, the concentration with time of necitumumab can be approximated with a biphasic decline. Data for a Population PK (POPPK) analysis was obtained from 5 clinical trials (including the Phase III studies SQUIRE and INSPIRE). The inter-patient variability was moderate to high for primary parameters. Necitumumab exhibits concentration-dependent clearance, possibly through target mediated drug distribution. The POPPK model confirmed that the time to reach steady state was approximately 100 days. Simulation of the clinical dosing regimen was associated with a minimum plasma concentration that was 5-fold greater than that expected for a therapeutic effect in the tissue compartment. In addition, the estimate of the half-life of necitumumab using the POPPK analysis was approximately double that obtained from the non-compartmental analysis. However, the higher POPPK estimate may have been influenced by drug accumulation over multiple doses. The choice of the current dosing regimen in the pivotal study appears to have been based on clinical factors (for example [e.g.], dose limiting toxicities) with limited PK data.

Across all clinical studies, a total of 1,056 patients had immunogenicity data reported. Based on the 861 patients who had both baseline and post-treatment samples for analysis, the rate of detection of anti-necitumumab antibodies (ADA) was low (8.6% of patients were post-treatment ADA-positive). Treatment-emergent ADAs were detected in 4.0% (34/861) of patients, and neutralizing antibodies were detected in 1.5% (13/861) of patients post-exposure to Portrazza. No analysis of treatment-emergent adverse events (TEAEs) in ADA-positive patients compared to TEAEs in ADA-negative patients was conducted. Based on data from the clinical studies SQUIRE and INSPIRE, no relationship was found between the presence of ADA and the incidence of infusion-related reactions.

Drug-drug interactions were examined in 35 patients with advanced solid malignancies who received necitumumab in combination with gemcitabine and cisplatin. The systemic drug exposure (geometric mean dose-normalized area under the curve [AUC]) of gemcitabine when given in the combination was increased by 18% and the maximum plasma concentration increased by 66% compared to administration of gemcitabine alone. However, the pharmacokinetics of cisplatin were unaltered when co-administered with necitumumab, and the pharmacokinetics of necitumumab were not affected when co-administered with gemcitabine and cisplatin.

The impact of necitumumab treatment on the QT/QTc interval was examined in 75 patients with advanced solid tumours. Patients were treated with necitumumab 800 mg once a week over a 6-week cycle. The study demonstrated lack of effect on QTc interval based on the criteria defined in International Council for Harmonisation (ICH) guidelines ICH E14. However, TEAEs of QTc prolongation were reported in one third of patients. QTc prolongation may be caused by electrolyte disturbances which are a known side effect of cytotoxic drugs and EGFR monoclonal antibodies.

Overall, the clinical pharmacological data support the use of Portrazza for the specified indication.

For further details, please refer to the Portrazza Product Monograph, approved by Health Canada and available through the Drug Product Database.

Clinical Efficacy

The clinical efficacy of Portrazza was primarily evaluated in a Phase III global, multicentre, open-label, two-arm, randomized study (SQUIRE) conducted in 1,093 patients with stage IV (American Joint Committee on Cancer Version 7) squamous non-small cell lung cancer (NSCLC), including patients with Eastern Cooperative Oncology Group Performance Status 2 (ECOG PS2), who had received no prior anticancer therapy for metastatic disease. Patients were randomized to receive Portrazza at 800 mg plus chemotherapy consisting of gemcitabine at 1,250 mg/m² and cisplatin at 75 mg/m² (Portrazza plus gemcitabine-cisplatin arm), or gemcitabine and cisplatin chemotherapy alone (control arm). Stratification factors were ECOG PS (0, 1 vs. 2) and geographic region (North America, Europe, and Australia vs. South America, South Africa, and India vs. Eastern Asia). Portrazza and gemcitabine were administered on Days 1 and 8 of each 3-week treatment cycle, and cisplatin was administered on Day 1 of each 3-week treatment cycle. There was no premedication for Portrazza mandated by the study. Pre-emptive treatment for skin reactions were not permitted prior to the beginning of the second treatment cycle. Patients received a maximum of six cycles of chemotherapy in each arm. Patients in the Portrazza plus gemcitabine-cisplatin arm who had no progression continued to receive single-agent Portrazza until disease progression or unacceptable toxicity. The primary efficacy endpoint was overall survival (OS) and the main secondary efficacy endpoints included progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). Patients underwent a radiographic assessment of disease status every six weeks, until radiographic documentation of progressive disease (PD). The primary outcome OS and the primary analysis was conducted with the intent-to-treat population of 545 patients in the Portrazza plus gemcitabine-cisplatin arm and 548 patients in the control arm.

The primary endpoint of OS improved among patients in the Portrazza plus gemcitabine-cisplatin arm compared with those in the control arm. Median OS was 11.5 months (95% confidence interval [CI]: 10.4, 12.6) in the Portrazza plus gemcitabine-cisplatin arm and 9.9 months (95% CI: 8.9, 11.1) in the control arm, a small improvement in median survival of 1.6 months. The associated hazard ratio (HR) was 0.84 (0.74, 0.96), with an estimated reduction in the risk of death of 15.8%. These results are statistically significant (p = 0.012). The Kaplan-Meier survival curves showed an early separation in favour of the Portrazza plus gemcitabine-cisplatin arm and the separation, albeit small, was maintained over the duration of the study follow-up. Therapy with Portrazza plus gemcitabine and cisplatin was also associated with a 4.9% improvement in one-year survival and a 3.4% improvement in 2-year survival. Pre-specified sensitivity analyses supported these results, and pre-specified subgroup analyses of OS generally favoured the patients treated with Portrazza, except for patients ≥70 years of age for whom there was no difference in OS between treatment groups.

The primary analysis of PFS showed a very slight improvement in median PFS of 0.2 months in favour of Portrazza-treated patients (5.7 months vs. 5.5 months). This result reached statistical significance (HR 0.85, [0.74, 0.98]; p = 0.02, associated with an estimated risk reduction of 14.9%). In addition, the observed clinical benefit was very small and the Kaplan-Meier curves showed a very small separation before 11 months of follow-up, after which time the curves came together. There was also a very small gain of 0.7 months in the median time to treatment failure among those treated in the Portrazza plus gemcitabine-cisplatin arm (4.3 months vs. 3.6 months) which was statistically significant (HR = 0.84; p = 0.006). A marginal improvement in ORR of 2.4% favouring the addition of Portrazza was not statistically significant (p = 0.4). Health status assessments used the self-administered Lung Cancer Symptom Scale (LCSS) and the European Quality of Life-5 Dimensions (EQ-5D). Overall, Portrazza in combination with gemcitabine and cisplatin was not associated with a compelling improvement or deterioration in health-related quality of life in these patients.

Supportive Studies

Three additional studies provided efficacy information:

• Study JFCK: A single cohort, open-label Phase II study (JFCK) of gemcitabine and cisplatin plus Portrazza as first-line therapy in patients with squamous NSCLC gave support for the efficacy of Portrazza in this combination.
• Study JFCL: A randomized, multicentre, open-label, Phase II study of paclitaxel-carboplatin chemotherapy plus necitumumab vs. paclitaxel-carboplatin chemotherapy alone in the first-line treatment of patients with Stage IV squamous NSCLC.
• INSPIRE Study: A randomized, multicentre, open-label Phase III study of pemetrexed-cisplatin chemotherapy plus necitumumab vs. pemetrexed-cisplatin chemotherapy alone in the first-line treatment of patients with Stage IV non-squamous NSCLC.

In Study JFCK, the ORR was 42.6% (all partial responses), while the median OS was 11.7 months, and the median PFS was 5.6 months. However, there was no evidence of treatment benefit in the supportive randomized study INSPIRE using Portrazza plus pemetrexed/cisplatin vs. the doublet alone, in patients with non-squamous NSCLC. In the randomized Phase II Study JFCL, the necitumumab plus paclitaxel-carboplatin combination resulted in an increased ORR suggesting an add-on effect over paclitaxel-carboplatin alone, for patients with squamous NSCLC; however, when tested, this result was not statistically significant.

Indication

The sponsor, Eli Lilly Canada, proposed the following indication:

• Portrazza (necitumumab) is indicated, in combination with gemcitabine and cisplatin, for the treatment of patients with locally advanced or metastatic squamous non-small cell lung cancer who have not received prior chemotherapy for this condition.

Given that the pivotal Phase III study population consisted of patients with stage IV NSCLC, Health Canada recommended the following indication:

• Portrazza (necitumumab) is indicated, in combination with gemcitabine and cisplatin, for first-line treatment of patients with locally advanced or metastatic squamous non-small cell lung cancer. Patients with locally advanced disease should be considered surgically incurable or incurable by virtue of ineligibility to receive curative surgery.

The recommended dose of Portrazza is 800 mg as a fixed dose intravenous infusion, combined with gemcitabine and cisplatin, on Day 1 and Day 8 of every 21 day cycle.

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

Clinical Safety

The clinical safety of Portrazza was primarily based on data from the SQUIRE study (see the Clinical Efficacy section), a Phase III, global, multicentre, two-arm, randomized, open-label study comparing Portrazza plus gemcitabine and cisplatin to gemcitabine and cisplatin alone in patients with squamous NSCLC. All patients had ECOG PS 0-2. Supportive studies (including INSPIRE, JFCL, and JFCK) provided additional safety data to establish the safety profile.

The safety population in the Phase III study SQUIRE consisted of 538 patients in the Portrazza plus gemcitabine-cisplatin arm and 541 patients in the gemcitabine-cisplatin control arm. The most frequently reported TEAEs of any grade that occurred in >5% of patients in the Portrazza plus gemcitabine-cisplatin arm were skin-related disorders or related events. A marked increase in any grade of TEAEs in the Portrazza plus gemcitabine-cisplatin arm compared to the control arm occurred as hypomagnesemia (29.6% vs. 15.2%) and weight loss (13.4% vs. 6.3%). Of the grade ≥3 TEAEs occurring in this group, those that were experienced as grade ≥3 more commonly in the Portrazza plus gemcitabine-cisplatin arm compared to the control arm were skin rash (3.7% vs 0.2%), hypomagnesemia (8.7% vs. 1.1%), vomiting (2.6% vs. 0.9%), and hypokalemia (3.0% vs. 1.5%). Grade ≥3 hypocalcemia developed in 1.5% of the patients in the Portrazza plus gemcitabine-cisplatin arm and only 0.4% in the control arm. A shift in magnesium levels during the study from grade 0-2 at baseline to grade 3-4 occurred in 17.8% of the patients in the Portrazza plus gemcitabine-cisplatin arm compared to 6.9% in the control arm. Similarly, the shift from grade 0-2 to grade 3-4 hypocalcemia occurred in 5.9% of the patients in the Portrazza plus gemcitabine-cisplatin arm and only 2.3% in the control arm. Further data on toxicities related to Portrazza can be found in the Adverse Reactions section of the Portrazza Product Monograph.

Risk of high-grade thromboembolic events (TEs) is associated with biologics in this class. The incidence of high-grade (Grade ≥3) TEs in the Portrazza plus gemcitabine-cisplatin arms of both the pivotal study, SQUIRE, and supporting study, INSPIRE, (8.9% and 10.2%, respectively) exceeded those that were reported in a meta-analysis of the Phase III cetuximab studies (7.4%). The Grade ≥3 TE rates for the Portrazza plus pemetrexed-cisplatin arm vs. the control arm in the INSPIRE study were 10.2% and 7.0%, respectively. The Grade ≥3 TE rates in SQUIRE were somewhat less in the Portrazza plus gemcitabine-cisplatin arm (8.9%) vs. in the control arm (4.6%). In SQUIRE, Grade ≥3 venous thromboembolic events (VTEs) occurred in 5.0% of the patients in the Portrazza plus gemcitabine-cisplatin arm and 2.6% of the patients in the control arm, with one fatal VTE in each arm. This compares to 7.6% Grade ≥3 VTEs in the Portrazza plus gemcitabine-cisplatin arm in INSPIRE (with three deaths or 1% attributed to pulmonary TEs and 3.5% (including 4 deaths or 1% attributable to pulmonary TEs) in the control arm. However, in SQUIRE, the Grade ≥3 arterial TE incidence was higher, with 3.9% of patients (0.4% fatality rate) experiencing events in the Portrazza plus gemcitabine-cisplatin arm compared to 2.0% (fatal in 0.2%) in the control arm. The analogous Grade ≥3 arterial TE rates in INSPIRE were 2.6% vs. 3.5%, respectively.

There was a higher rate of sudden death or a potential association of death with TE in the INSPIRE study. In the SQUIRE study, unexplained death or sudden death occurred in 1.9% and 0.4% of patients in the Portrazza plus gemcitabine-cisplatin arm and control arm, respectively. When cases clearly associated with progressive disease were removed from these groups on review of the narratives of these cases, 1% vs. 0.2% of unexplained cases remained in the respective treatment arms. Comparing fatalities associated with severe infection in the Portrazza plus gemcitabine-cisplatin arm vs. the control arm, upper respiratory tract bacterial infection and pneumonia occurred together in 1.1% vs. 0.6% while sepsis occurred in 0% vs. 0.4%, respectively.

Appropriate warnings and precautions are in place in the approved Portrazza Product Monograph to address the identified safety concerns.

The following warnings have been included in a Serious Warnings and Precautions box in the Product Monograph for Portrazza: increased frequency of cardiorespiratory arrest or sudden death, increased risk of venous or arterial thromboembolic events, and increased risk of electrolyte disorders (magnesium, calcium, potassium, and/or phosphate).

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

Supportive Studies

As with the efficacy data, Studies JFCK, JFCL, and INSPIRE provided supportive safety data.

The safety profile of Portrazza was consistent across the supportive studies. Electrolyte deficiencies were common TEAEs in all of the studies. Hypomagnesemia was the most common of these disorders, with the incidence ranging from 24.5% to 34.4% (all grades) in three NSCLC studies. Hypocalcemia and hypokalemia were also more common in regimens containing Portrazza compared to controls and occasionally these electrolyte deficiencies occurred concurrently, requiring increased clinical vigilance for signs of clinical consequences. Hypersensitivity/infusion-related reactions were of low frequency, varying from 2.0% to 6.8% across the supportive studies. These reactions were generally manageable. Hematological toxicity was somewhat more common, with an increase in grade 3/4 neutropenia when Portrazza was added to doublet chemotherapy (e.g., 30.2% vs. 23.6% in the randomized Phase II JFCL study). Similarly, grade ≥3 infections were more commonly associated with the use of Portrazza (e.g., 11.5% vs. 5.4% in the INSPIRE study and 17.9% vs. 12.7% in the JFCL study), including neutropenic sepsis and respiratory failure (2.0% vs. 0.3% for the former and 1.0% vs. 0.3% for the latter in the INSPIRE study).

Fatal cardiac events and sudden death occurred infrequently but were more frequent with therapy including Portrazza, particularly in the INSPIRE study (2.3% vs. 0.6%).

The data from the supportive studies support the SQUIRE pivotal study in highlighting the delicate balance between a small survival advantage associated with therapy containing Portrazza and the increased risks of some formidable adverse events.