Summary Basis of Decision for Vectibix ™

3.3.1 Pharmacodynamics

Vectibix™ (20 mg/mL, panitumumab) is an antineoplastic. Vectibix™ is a fully human IgG2 monoclonal antibody that is directed against the EGFR, a cell surface transmembrane receptor over expressed in certain tumour types. Panitumumab binds to the EGFR extracellular domain, thereby preventing the interaction of the receptor with EGFR ligands.

The binding of panitumumab to EGFR inhibits the growth and survival of the tumour cells expressing EGFR.

The clinical activity and safety of panitumumab were evaluated in several Phase II studies in subjects with various tumour types (e.g. colorectal cancer (CRC), prostate cancer, renal cell cancer, and non-small cell lung cancer), either as a single agent or in a combination with chemotherapy. Based on evidence that panitumumab had the most promising clinical activity in subjects with metastatic colorectal carcinoma (mCRC), this indication was selected for further development.

3.3.2 Pharmacokinetics

Both standard and population PK studies were conducted. Pharmacokinetic profile of panitumumab was assessed in multiple clinical studies over a wide range of doses. Following a single-dose administration, panitumumab exhibited nonlinear pharmacokinetics in a weekly dose range of 0.75 to 9 mg/kg, with the area under the curve (AUC) increased in a greater than dose-proportional manner and clearance decreased with increasing dose, which was believed due to progressive saturation of the EGFR. This nonlinearity, however, was less apparent at dose >2 mg/kg.

PK profile following multiple dose administration (e.g. 6 mg/kg once every other week as 1-hour IV infusion) did not show significant accumulation of panitumumab over the study period of 10 weeks

Pharmacokinetic steady-state is reached after 3 doses at 6 mg/kg given once every 2 weeks without a loading dose. The PK parameters of panitumumab at steady state are summarized in the following table.

C_max = maximum serum concentration; C_min = minimum serum concentration; AUC_0-tau = area under the curve for the dosing interval; t_1/2 = half-life during the dosing interval; CL = serum clearance.

Population PK analysis did not indicate significant effect of covariates, including age, gender, race, mild-to-moderate renal dysfunction, and mild-to-moderate hepatic dysfunction, on the PK profile of panitumumab.

3.3.3 Clinical Efficacy

Pivotal study 20020408 was an open-labelled, randomized, Phase III clinical trial. This study was conducted to evaluate the use of Vectibix™ (panitumumab) plus Best Supportive Care (BSC) versus Best Supportive Care (BSC) in subjects with mCRC. The purpose of this study was to assess whether Vectibix™ plus BSC was more effective than BSC alone in subjects with EGFR expressing mCRC who failed standard chemotherapy with fluoropyrimidines, irinotecan and oxaliplatin.

The results demonstrated a marginal improvement (0.7 weeks increase) in median progression free survival (PFS) time, the primary endpoint, for the Vectibix™ plus BSC group (8.0 weeks) compared with the BSC alone group (7.3 weeks). Compared with BSC alone, the rate of disease progression or death was reduced by 46% in the Vectibix™ plus BSC group (hazard ratio = 0.542).

After having reviewed the results of the clinical data and in particular the results of the pivotal study 20020408, the clinical review team concluded that a meaningful clinical benefit was not demonstrated from the data submitted, mainly due to issues in design and conduct of the pivotal trial. Two main issues were raised in relation to the efficacy of Vectibix™ in refractory patients with mCRC:

1. Though achieving a statistically significant median PFS (the Primary Objective) in patient receiving Vectibix™ with BSC vs. BSC alone, the extent of benefit (i.e. difference in median PFS of 0.7 weeks) was not considered to be clinically significant.
2. Efficacy data indicated that a subgroup of patients might have benefited from the therapy with Vectibix^TM. Such a subgroup was not readily identified prospectively in the study and the evaluation of EGFR by immunohistochemistry was not found to be a reliable marker. New markers for efficacy prediction were needed.

The sponsor performed a retrospective sub-group analysis based on the status of the KRAS gene from the resected tumour tissue. The patients with available KRAS testing results (n=427, 92% of total patients in the pivotal trial) were divided into two groups based on mutation status of KRAS: wild type KRAS (n=243) and mutated KRAS (n=184) using an allele-specific polymerase chain reaction. The results indicate that the hazard ratio was 0.45 in the KRAS wild-type group and 0.99 in the KRAS mutant group. Within the wild-type KRAS stratum, there was a statistically significant difference in PFS in favour of Vectibix™. The increase in median PFS in Vectibix™ treatment group in the KRAS wild-type stratum was 5 weeks, a clinically meaningful increase in this patient population. The difference in median PFS in the KRAS mutant group was 0 weeks. The PFS rates at the first scheduled visit (week 8) in the KRAS wild-type group were 59.7% on Vectibix™ plus BSC and 21.0% on BSC alone, a difference of 38.7%. In the KRAS wild type group, the response rate was 17% for Vectibix™ and 0% for BSC. There were no differences in overall survival seen in either group; however, approximately three quarters of patients randomized to the BSC arm went on to receive panitumumab on a cross-over protocol. Based on the information resubmitted by the sponsor, Vectibix™ was granted a Notice of Compliance under the Notice of Compliance with Conditions Policy for use in the treatment of mCRC after failure of fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens. The use of Vectibix™ should be limited for use in patients with wild type KRAS.

In the post-marketing phase, the sponsor should address the following issues:

• Evidence of survival benefit from the use of Vectibix™ in mCRC
• Demonstration in a prospective manner the predictive value of KRAS in the management of patients with mCRC receiving panitumumab
• An appropriate methodology for the accurate evaluation of KRAS in patients with mCRC

The results from the sub-group analysis indicate that the clinical benefit of Vectibix™ treatment, as measured by median PFS, hazard ratio, and response rate, was observed from KRAS non-mutated (wild-type) patients. The results are promising for treatment of mCRC patients after failure of fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.

3.3.4 Clinical Safety

To investigate the safety of Vectibix™, the safety data was combined from clinical studies in three different settings: 1) subjects with mCRC receiving Vectibix™ monotherapy (n= 789); 2) subjects receiving Vectibix™ monotherapy, which included subjects with mCRC and other solid tumours (n=1130); and 3) subjects treated with Vectibix™ combination therapy (n=174).

The safety profile of Vectibix™ in patients whose tumours expressed KRAS wild-type (n=123) was generally consistent with overall mCRC monotherapy set. In the randomized controlled trial, all 123 patients (100%) with non-mutated (wild-type) KRAS status treated with Vectibix™ experienced adverse reactions, of which 62% were reported as Grade 3-4 events.

The following adverse events were of special interest for Vectibix™: integument and eye-related irritations, gastrointestinal effects, hypomagnesemia, pulmonary effects, cardiovascular effects, infusion reactions, and immunogenicity reactions.

Integument and Eye-related Irritations

The most frequently occurring adverse event with the use of Vectibix™ was skin and eye toxicity. It has been demonstrated that EGFR is an important regulator of keratinocyte biology and homeostasis of hair follicles, and skin toxicity has been considered a marker of biological activity for EGFR inhibitors.

Integument and eye toxicities were reported in 91% of the subjects receiving Vectibix™. Approximately half were reported to have skin-related adverse events of acneiform dermatitis (52%), pruritus (49%), or erythema (47%). Other skin toxicities included rash (37%), skin exfoliation (22%), paronychia (19%), and dry skin or skin fissures (15% each). Most subjects (626/721, 87%) with integument- and eye-related toxicities had events that were mild or moderate in intensity. However, Vectibix™ administration was reinstated after improvement of skin toxicity in 72% of these subjects, indicating that skin toxicity is reversible and can be effectively managed by skipped doses or dose reductions. Skin and eye toxicities were observed relatively soon after initiation of Vectibix™. The median to first integument- and eye-related toxicity was reported at Day 10. Eye toxicities were reported in 15% of the subjects. Conjunctivitis was reported in 37 subjects (5%).

Gastrointestinal Effects

Stomatitis and oral mucositis were reported in 14% of the subjects (7% considered related to Vectibix™). Events were mild or moderate in 98% of the subjects. Diarrhea was reported in 29% of subjects (13% related to Vectibix™) and most (93%) were mild or moderate in severity. There were 15 subjects (2%) that had diarrhea classified as severe. Dose alteration and study discontinuation due to diarrhea each occurred in 1 subject (<1%).

Hypomagnesemia

Administration of other anti-EGFR antibodies has been associated with hypomagnesemia. Although the pathogenesis is not fully understood, EGFR is strongly expressed in the kidney (particularly in the ascending limb of the loop of Henle), and EGFR blockade may interfere with magnesium transport in this region where 70% of filtered magnesium is reabsorbed. However, alteration of magnesium absorption in the intestine cannot be excluded.

Vectibix™ was associated with decreases in serum magnesium. Overall, 39% of subjects with normal magnesium levels at baseline had decreases in serum magnesium levels of any grade; 25% of the 649 subjects with serum magnesium assessments had mild decreases after initiation of Vectibix™ and 8% had moderate decreases. Seven subjects (1%) had serious adverse events of hypomagnesemia. However, Grade 3 or 4 levels were observed in only 5% of the subjects. Most of the decreases in serum magnesium were asymptomatic, and hypomagnesemia responded promptly to IV magnesium administration. Fatigue, muscle spasms, neuropathy, and peripheral neuropathy were each reported with a slightly higher incidence in subjects for whom an adverse event of hypomagnesemia was also reported.

Monitoring of hypomagnesemia and hypocalcemia is recommended as a precaution during treatment with Vectibix™. Furthermore, monitoring for a period of 8 weeks following the last dose of Vectibix™ is also recommended, based on the period of time specified for other anti-EGFR agents.

Pulmonary Effects

Interstitial lung disease (ILD) has been observed in patients who undergo treatment that induces EGFR inhibitors. No cases of ILD were reported as adverse events with the use of Vectibix™. Pneumonitis or lung infiltration were reported for 3 subjects (0.4%); however, none of these events were ≥Grade 3 in severity or considered treatment related. The subjects in the mCRC monotherapy group participated in studies that excluded subjects with a history or baseline CT scan evidence of interstitial pneumonitis or pulmonary fibrosis. A total of 27% of the subjects had pulmonary adverse events, however most had events that were mild or moderate intensity. Thus, Vectibix™ administered, as a single agent, did not appear to significantly increase the risk for pulmonary toxicity (particularly pneumonitis or lung infiltration) or vascular toxicity (particularly arterial or venous thromboembolic events).

Cardiac Effects

Multiple-gated acquisition (MUGA) scans and cardiac enzyme levels (CPK-MB and troponin-T) were collected for 331 subjects enrolled in earlier studies. Only 5 subjects (<1%) experienced events associated with cardiac function that led to either discontinuation or interruption of treatment, while no events led to an alteration of the dose. These data suggest that treatment with Vectibix™ does not result in cardiac toxicity.

Infusion Reactions

In clinical studies, potential infusion reactions (occurring within 24 hours of the first dose), which may include symptoms/signs such as chills, fever or dyspnea, were reported in <2% of Vectibix™-treated patients, of which <1% were severe (Grade 3) and <0.2% resulted in discontinuation of Vectibix™. Most of the symptoms of potential infusion reactions were mild in intensity and were resolved without treatment. They were isolated occurrences and did not require alteration or interruption of Vectibix™ administration.

Immunogenicity Reactions

Immunogenicity testing using two assay platforms (acid-dissociation ELISA and Biacore) indicated that the overall incidence of a post-dose anti-panitumumab antibody response was low (< 5% of subjects examined with postdose time points). Postdose neutralizing antibodies were detected in 1 of 447 subjects (0.2%) and 7 of 447 subjects (1.6%) tested by each of the two assays. A review of adverse events and other safety parameters, and efficacy for these subjects indicated no apparent correlation between the presence of a post-dose human anti-human antibody (HAHA) response against Vectibix™ and observed safety and efficacy outcomes.

In conclusion, Vectibix™ was well tolerated after an overall analysis of safety. The main toxicities demonstrated were related to the known pharmacologic effects of the class of the EGFR inhibitors, particularly in terms of skin toxicity and hypomagnesemia. Other possible toxicities related to the use of the class of drugs such as cardiac, vascular and pulmonary toxicities, were not substantiated in the data presented. An important potential safety benefit from Vectibix™ is the fact that it is a human monoclonal antibody with potentially less effect on antibody-related toxicities (i.e. infusion reactions and development of neutralizing antibodies). In both instances this was not significant and therefore adds value to the use of this drug. However, further monitoring over longer periods is warranted and should be undertaken in a post-marketing phase.

3.3.5 NOC/c Commitments (Notice of Compliance with Conditions)

The commitments for authorization under the Notice of Compliance with Conditions (NOC/c) Policy were discussed in a teleconference between Health Canada and the sponsor on Feb 19, 2008. Consistent with the NOC/c policy, the sponsor has agreed to submit the results of the following confirmatory studies:

1. Provide information on the confirmatory trials to investigate efficacy and safety of Vectibix™ in relation to non-mutated (wild-type) KRAS in mCRC patients (such as studies 20050181 and 20050203), including:
   • Information on the current status and the proposed milestones for the studies;
   • Study protocols and protocol amendments as a part of the response to the NOC/c-Qualifying Notice;
   • The statistical analysis plan (SAP) that describes the analysis of the wild-type KRAS sub-population in these studies, when available. Any input provided by other regulatory agencies on the SAP should be provided and amendments that have been made to the original SAP should be clearly highlighted. The reasons for the amendments should also be provided;
   • The interim, if any, and final clinical study reports, including the efficacy and safety analysis in relation to KRAS; data on quality of life; the proposed timelines for submitting these reports; and the timelines for the completion of these studies;
   • Data on the efficacy and safety of Vectibix™ in relation to KRAS in special populations of interest within the clinical study reports, for example, geriatrics.
2. Provide results from the retrospective analysis of efficacy and safety of Vectibix™ based on the KRAS status of patients, from the non-pivotal clinical studies 20030167 and 20030250 in a Supplemental New Drug Submission (SNDS). A time line for this SNDS should be indicated.
3. Ensure that the KRAS testing kit is available in Canada before launching the product.
4. Update the Product Monograph with information on the KRAS testing kit and state that only the testing kits that have been validated and authorized by Health Canada can be used.
5. Provide information on other on-going trials with Vectibix™ for the relevant indications including, but not limited to, the STEPP trial, SPIRITT trial and PRECEPT trial. Results of retrospective or prospective analysis of efficacy of Vectibix™ in relation to the KRAS mutation status of mCRC patients from these studies should be submitted. The proposed timelines for submitting the study reports should be specified.
6. Provide safety updates for all on-going Vectibix™ trials.
7. Provide information in relation to communications and consultations with other agencies, when available.
   
   The following issues pertaining to the Post Market Safety Monitoring should be addressed:
8. Provide reports of all serious Adverse Reactions (AR) that occur in Canada and all serious unexpected ARs that occur outside of Canada. These should be forwarded within 15 days to Health Canada. One copy should be provided to the Marketed Health Products Directorate and another copy to the Centre for the Evaluation of Radiopharmaceuticals and Biotherapeutics in the Biologics and Genetic Therapies Directorate in accordance with current regulations and guidelines (e.g. Guidelines for Reporting Adverse Reactions to Marketed Drugs and the Guidance for Industry: Notice of Compliance with Conditions).
9. Submit Periodic Safety Update Reports for NOC/c Products (PSUR-Cs) for Vectibix™ on a semi-annual basis until such time as conditions associated with the market authorization are removed. PSUR-Cs should be prepared in accordance with the E2C ICH Guideline, including format and content, as per Section 6.2.2 of the Guidance for Industry, Notice of Compliance with Conditions (NOC/c).
10. Implement the Risk Management Plan (RMP) in Canada and provide any updates to the RMP when available.
11. Comply with the notification and reporting of specific issues of concern as outlined in Section 6.2.4 of the Guidance for Industry: Notice of Compliance with Conditions and section 6Eiii of the NOC/c policy.
    
    The following outstanding/additional issues should be addressed:
12. Provide a complete listing of ongoing additional clinical trials related to Vectibix™, appended to the draft Letter of Undertaking, as per Section 4.5 of the Guidance for Industry: Notice of Compliance with Conditions.
13. Provide copies of any marketing authorizations or other regulatory actions for Vectibix™ from any other drug regulatory authority as per Section 4.6 of the Guidance for Industry: Notice of Compliance with Conditions.