Summary Basis of Decision for Giotrif

Clinical Pharmacology

Metastatic adenocarcinoma of the lung is a life-threatening, incurable disease with poor long-term survival.

Afatinib (Brand name: Giotrif) is an, irreversible inhibitor of, human epidermal growth factor receptor (ErbB1), HER 2 (ErbB2), and HER 4.

The clinical pharmacology program included human pharmacodynamics and pharmacokinetic studies.

Giotrif exhibited non-linear pharmacokinetics; more than proportional increases in exposure were observed with increasing dose in the clinical dose range. Afatinib was excreted primarily unchanged via the biliary/fecal route, consistent with in vitro studies that demonstrated an absence of interaction with CYP 450 enzymes.

Patients with moderate renal impairment may have increased toxicities due to higher systemic exposure to afatinib at the recommended dose of 40 mg once daily. Conversely, administration of afatinib with food significantly decreased exposure. The effects of severe renal and hepatic impairment on the PK parameters of afatinib have not been studied. This data deficiency is captured in the PM.

Together, the clinical and pharmacological data support the use of Giotrif for EGFR TKI-naïve patients with metastatic adenocarcinoma of the lung harboring activating EGFR mutations. Definition of special populations for which exposure is significantly altered or in whom exclusion is appropriate have been considered and adequately addressed in the Giotrif Product Monograph.

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

Clinical Efficacy

The clinical efficacy of Giotrif was primarily evaluated in four key studies: LUX-Lung 3 (pivotal), LUX-Lung 2, LUX-Lung 1, and LUX-Lung 5.

The LUX-Lung 3 and LUX-Lung 2 studies enrolled patients with EGFR mutation-positive adenocarcinoma who were not previously treated with an EGFR TKI (i.e., EGFR TKI-naïve patients). In contrast, LUX-Lung 1 and LUX-Lung 5 enrolled patients who had received previous EGFR TKI (i.e., EGFR TKI-treated patients).

The pivotal LUX-Lung 3 study was a global, randomized, multicenter, open-label Phase III study comparing efficacy and safety of Giotrif monotherapy with standard cisplatin/pemetrexed doublet chemotherapy in patients with locally advanced (Stage IIIB) or metastatic (Stage IV) adenocarcinoma of the lung harboring activating EGFR mutations. A total of 345 patients were randomized (2:1) to receive once daily oral Giotrif 40 mg until disease progression or intolerance, or standard cisplatin/pemetrexed chemotherapy up to 6 cycles. The study was conducted in the first-line setting, i.e., eligible patients could have not received prior systemic chemotherapy for advanced disease or prior EGFR TKI for any disease stage. The primary study endpoint was progression-free survival (PFS) and key secondary endpoints included objective response rate (ORR) and overall survival (OS).

Among the patients randomised, 65% were female, the median age was 61 years, 26% were Caucasian and 72% were Asian, the baseline ECOG performance status was 0 in 39% and 1 in 61%,. The majority of the patients (89%) had the two common EGFR mutations (del19 and L858R) with 11% having other less common mutations. Patients with active brain system metastases (i.e., stable <4 weeks and/or symptomatic and/or requiring treatment with anticonvulsants or steroids and/or leptomeningeal disease) were excluded from the study.

Results from the LUX-Lung 3 study demonstrated a statistically significant improvement in PFS (the primary efficacy endpoint) in the Giotrif treatment group compared to the control chemotherapy treatment group. The median PFS was 11.1 months for Giotrif-treated patients vs. 6.9 months for chemotherapy-treated patients. Objective response rate was higher in the Giotrif group (56.1%) compared to the chemotherapy group (22.6%). This magnitude of PFS benefit is considered clinically meaningful.

Based on an updated OS analysis when 175 patients had died, median OS was 28.1 months and 28.2 months in the Giotrif and chemotherapy groups, respectively. The OS results neither demonstrated a significant OS benefit nor indicated an apparent detrimental effect on OS by Giotrif therapy vs. control chemotherapy. Due to the study design, OS results may be limited by a lack of statistical power and confounded by uncontrolled use of post-progression anti-neoplastic therapies, including other EGFR TKIs and chemotherapy agents. The lack of OS benefit was captured prominently in the Giotrif Product Monograph to inform prescribers of this limitation of the efficacy dataset supporting the authorized indication and clinical use.

A total of 4 patients met the pre-defined criteria (displaying minimum treatment-related toxicities after first treatment cycle) for a dose-escalation of Giotrif from 40 mg to 50 mg. The patient number was considered insufficient to permit meaning efficacy assessment for the dose escalation scheme. Taking into consideration the potential of increased toxicities with increasing Giotrif dosage, such a dose escalation scheme is not included in the Giotrif PM.

In a pre-specified subgroup analysis based on EGFR mutation subtypes (common mutations vs. uncommon mutations), PFS and OS were in favor of the chemotherapy treatment among patients whose tumor harbored uncommon EGFR mutations [Hazard Ratio (HR) 1.9 and 3 for PFS and OS, respectively]. This subgroup was small [Number of patients (N) = 37 patients] and genetically heterogeneous (10 different molecular subtypes with unequal distribution between the two study groups), which limits the value and interpretation of pooled analyses based on the entire subgroup. Therefore, the clinical efficacy of Giotrif was assessed by each mutation subtype in this subgroup. Among 26 patients treated with Giotrif, 4 achieved a partial response (all of 6 months or greater duration), although the antitumor activity of Giotrif appeared to be more limited in those with the T790M mutation, with only one response in a total of 11 patients. This level of tumor response in those with uncommon mutations may be clinically meaningful, taking into consideration limited therapeutic options for these patients and the rarity of the disease (uncommon EGFR mutations represent approximately 10% of all EGFR mutations in NSCLC). Therefore, Health Canada did not recommend that this patient subpopulation be explicitly excluded from the authorized indication. In the Giotrif PM, it is prominently captured that safety and efficacy of Giotrif have not been established in patients with uncommon EGFR mutations; and that data are more limited in patients with tumors with the T90M mutation. Mutation-specific objective tumor responses are also listed.

The LUX-Lung 2 study was an open label, single arm, Phase II study which investigated the efficacy and safety of Giotrif as a monotherapy in EGFR TKI-naïve patients with metastatic adenocarcinoma of the lung harboring EGFR-activating mutations.

A total of 129 patients entered the LUX-Lung 2 study and were enrolled into four key cohorts defined by the starting dose of Giotrif (40 mg or 50 mg daily) and line of therapy [first-line (N = 61) or second-line setting (N = 68) (i.e., after failure of one prior chemotherapy regimen)] to receive Giotrif starting dose of 40 mg or 50 mg daily.

The primary efficacy endpoint was overall response rate (ORR). Results of this study demonstrated anti-tumor activity of Giotrif in patients with EGFR mutations in the first-line or second-line setting. Study data indicated that the 40 mg Giotrif starting dose is associated with comparable best overall response and better tolerability compared with the 50 mg Gitorif starting dose for protracted treatment with Giortif in a population of EGFR TKI-naïve patients. Efficacy results of the LUX-Lung 2 study supported the tumor response data in the pivotal study.

LUX-Lung 1 was an international, multicentre, randomized, double-blind Phase IIb/III trial comparing the efficacy and safety of Giotrif (50 mg daily) plus best supportive care (BSC) vs. placebo plus BSC in patients with metastatic adenocarcinoma of the lung failing previous reversible EGFR TKIs, [for example (e.g.), erlotinib, gefitinib]. A total of 585 patients were randomized (2:1) to receive Giotrif or placebo treatment. Confirmation of EGFR mutation status was not required before study treatment. All patients had undergone at least 12 weeks of prior therapy with a reversible EGFR TKI and a prior systemic chemotherapy.

This study showed similar survival between treatment groups, with a median OS of 12.0 months for placebo and 10.8 months for Giotrif  (HR 1.08; 95% CI 0.86, 1.35) and did not meet its pre-specified primary endpoint. Despite this, secondary endpoints were analyzed; based on the independent assessment, median PFS was 3.3 months in the Giotrif arm vs. 1.1 months in the placebo arm (HR 0.38, p<0.0001). While this HR was considered promising, the absolute magnitude 2-3 months improvement in median PFS was considered modest. The great majority of best overall tumor response was stable disease, in contrast to the high ORR in EGFR TKI-naïve patients in the pivotal LUX Lung 3 study.

LUX-Lung 5 study was a Phase III randomised trial of Giotrif plus weekly paclitaxel vs. the investigator's choice of chemotherapy following Giotrif monotherapy in patients with metastatic adenocarcinoma of the lung failing previous erlotinib or gefitinib treatment. Only the interim report of the LUX-Lung 5 study was submitted including data from Part A of the study in which all patients received Giotrif monotherapy (starting dose 50 mg). Enrolled patients were not required to have analysis of tumour samples for EGFR mutation status.

The primary endpoint was PFS based on investigator assessment. A total of 1,154 patients were entered into the study and received Giotrif treatment. Results for mutation status were available for only 84 patients, 49 patients (58.3%) were mutation positive and 35 patients (41.7%) were mutation negative. At the interim analysis, 872 PFS event had occurred (76%). The median PFS was 3.3. Median PFS was longer in patients whose tumors harbored EGFR mutations (4.2 months) than in mutation negative patients (2.6 months).

Overall, the clinical benefit of Giotrif among EGFR TKI-naïve patients is considered significant, based on the PFS and ORR results in the pivotal LUX-Lung 3 and supportive LUX-Lung 2 study. The clinical benefit of Giotrif among patients who failed a prior EGFR TKI (i.e., EGFR TKI-treated patients) is unclear. This is because the LUX-Lung 1 did not meet its primary efficacy endpoint, i.e., it did not demonstrate a significant improvement in OS in the Giotrif group compared with the placebo group. The level of tumor control (based on PFS and ORR) in the LUX-Lung 1 study in the context of a negative primary efficacy analysis, is not considered substantial evidence of clinical benefit. Giotrif was not authorized for use in EGFR TKI-treated patients with metastatic adenocarcinoma of the lung harboring activating EGFR TKIs. This is reflected in the indication in the approved PM.

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

Clinical Safety

The overall safety profile of Giotrif is based on results of four key studies [LUX-Lung 3 (pivotal), LUX-Lung 2, LUX-Lung 1, and LUX-Lung 5], as well as pooled safety results from different cohorts, e.g., those received 40 mg Giotrif monotherapy, 50 mg monotherapy, 40 or 50 mg monotherapy, and Giotrif at any dose as either monotherapy or in combination.

The adverse event (AE) analyses in the pivotal study were primarily based on treatment-emergent AEs (i.e., events with an onset between the start of study drug and 28 days after stopping it).

Virtually all patients in the pivotal LUX-Lung 3 study (described in Clinical Efficacy) experienced at least one AE during the study. Giotrif demonstrated a different AE profile compared to control chemotherapy: the most common AEs of any Common Terminology Criteria Adverse Events (CTCAE) Grade in the Giotrif arm were diarrhea (96.1% of patients), rash/acne (90.0%)¹, stomatitis (73.4%)¹, and nail effect (61.6%)¹. These AEs were also the most frequent CTCAE Grade 3 events (rash¹ 16.2%, diarrhoea 14.8%, nail effect¹ 11.8% and stomatitis¹ 8.3%). In the chemotherapy treatment group, the most frequently reported AEs were nausea (67.6% of patients), decreased appetite (55.0%), and fatigue¹ (49.5%). The most frequent AEs of CTCAE Grade 3 in this control group were neutropenia (16.2% of patients), fatigue (12.6%), and leukopenia (8.1%).

Serious AEs were reported in 28.8% patients in the Giotrif treatment group, compared with 22.5% in the chemotherapy treatment group. The most frequent serious AEs in Giotrif-treated patients were: diarrhea; vomiting; dyspnea; fatigue; dehydration; pneumonia; and stomatitis. Fatal adverse events related to Giotrif included one event each of dyspnea, acute respiratory distress syndrome (ARDS) [interstitial lung disease (ILD)-like], sepsis, and death (not otherwise specified).

A pre-defined, AE severity (CTCAE Grade) -based Giotrif dose adjustment scheme was implemented in the pivotal study. Dose reductions due to AEs occurred in 57.2% of Giotrif-treated patients versus 16.2% in chemotherapy-treated patients. The very common AEs (>10%) leading to dose reduction in patients treated with Giotrif included diarrhea, rash/acne, paronychia, and stomatitis. Permanent study treatment discontinuation occurred in 14.0% of patients in the Giotrif treatment group and 15.3% in the chemotherapy treatment group. The common AEs which led to discontinuation in the Giotrif were: diarrhea, dyspnea; and ILD. This Giotrif dose adjustment scheme, in addition to other risk mitigation strategies (e.g., proactive treatment of diarrhea) appeared to be effective in managing severe and/serious AEs, as dose reduction of Giotrif was associated with a lower frequency of common adverse events, e.g., after first-dose reduction, the frequency for diarrhea decreased from 96% to 52%. The median treatment duration at reduced dose levels (30 mg - 140 days; 20 mg - 277 days) were longer than the starting 40 mg dose (85 days), indicating that many patients tolerated Giotrif at reduced doses and likely benefited from the dose reduction by staying on the treatment at lower doses longer.

Afatinib inhibits HER2 and left ventricular dysfunction has been associated with HER2 inhibition. In the pivotal trial routine left ventricular ejection fraction (LVEF) monitoring was not compulsory in the chemotherapy treated patients and therefore only approximately 14% had an on treatment LVEF assessment compared to 91% of Giotrif-treated patients. With a mean total treatment time of 11 months, 31% of Giotrif- treated patients had a decrease of LVEF of >10% from baseline; and with mean total treatment time 2.8 months 13% of pemetrexed/cisplatin-treated patients had such a decrease. Giotrif has not been studied in patients with an abnormal LVEF or those with a significant cardiac history. In patients with cardiac risk factors and those with conditions that can affect left ventricular function, cardiac monitoring, including an assessment of LVEF at baseline and during Giotrif treatment, should be considered.

The safety profile of Giotrif at a starting dose of 40 mg daily in the supportive LUX-Lung 2 study (described in Clinical Efficacy) was generally consistent with that in the pivotal study. However, severe and serious AEs appeared to be more frequent in the 50 mg cohort compared with the 40 mg cohort. Adverse events of CTCAE Grade 3 were 43.3% in the 40 mg starting dose group and 58.6% in the 50 mg starting dose group. Adverse events of CTCAE Grade 5 were reported in 9.3% of patients overall, including 6.7% of patients in the 40 mg starting dose group and 10.1% of patients in the 50 mg. These observations raised the safety concern for the dose escalation scheme in the pivotal study (described in Clinical Efficacy). Considering limited efficacy evidence supporting Giotrif dose escalation from 40 mg to 50 mg and this safety concern, such a dosage scheme is not included in the Giotrif PM.

Compared to the placebo group, AEs and serious AEs in the LUX-Lung 1 study (described in Clinical Efficacy) were substantially increased in the Giotrif treatment group. Adverse events considered related to the study medication were reported by 95.4% of patients in the Giotrif group and 37.9% of patients in the placebo group. Adverse events of CTCAE grade 3 or higher were reported for 56.7% of patients in the Giotrif group and 24.6% of patients in the placebo group. Study drug was permanently discontinued due to AEs in 17.9% of patients in the Giotrif group and 6.2% of patients in the placebo group. Drug-related serious AEs were reported for 39 patients (10.0%) in the Giotrif group and one patient (0.5%) in the placebo group. More patients (78.9%) in the placebo arm received non-study anti-cancer therapy following their disease progression, compared with 67.6% in the Giotrif group.

Almost all patients (99.0%) experienced at least one treatment-emergent AE in the LUX-Lung 5 study (described in Clinical Efficacy). The most frequent AE was diarrhea (85.2%), followed by rash (69.5%) and stomatitis (50.8%). The highest CTCAE Grade of AEs was grade 3 in 39.9% of patients; grade 4 in 5.2% of patients; and grade 5 in 15.9%. Giotrif-related AEs leading to discontinuation occurred in 11.7% of patients, with diarrhea and rash as the most frequent events. Serious AEs occurred in 38.9% of patients, including 10.4% with related serious AEs. In 11 patients (1.0%), AEs leading to death were considered drug-related.

More adverse events ≥ CTCAE Grade 3 were reported for patients ≥ 65 years than patients < 65 years in clinical trials.

Overall, Giotrif monotherapy was associated with significant risks of adverse events, some of which were serious and fatal. However, with pre-defined, AE severity-based Giotrif dose adjustment in combination with proactive AE management and proper patient selection (especially for diarrhea), Giotrif-related AEs appeared to be largely manageable. Giotrif-related deaths were uncommon in the pivotal study.

Successful management of AEs is essential for the success of Giotrif treatment (maintaining an acceptable benefit/risk profile for Giotrif). The following are highlights of the measures undertaken by Health Canada to improve the risk communication and mitigation with regard to Giotrif-related toxicities:

1. The proposed PM provided by the sponsor was revised per Health Canada's recommendations to improve communication of significant risks identified in clinical trials, including creating a Serious Warnings and Precautions Box for diarrhea, severe skin toxicities, interstitial lung disease and hepatotoxicity.
2. The approved PM contains an explicit warning against Giotrif use in patient subgroups that may be at particular risk of severe and/or serious AEs related to Giotrif, including those with recent or ongoing gastrointestinal disorders, those with severe renal and/or hepatic impairment, and those who develop cardiac signs/symptoms during Giotrif treatment.
3. Risk management recommendations, based on the protocol of pivotal study, were enhanced in the PM, especially for diarrhea. Giotrif-related diarrhea occurred in virtually all patients and was the leading Giotrif-related severe AE, serious AE, and AE resulting in dose reduction. Close monitoring and proactive management of diarrhea is essential for successful Giotrif treatment. Accordingly, diarrhea was managed in clinical trials by proactive anti-diarrheal treatment and by following a severity-based dose reduction scheme. In the clinical trials, patients played an important role in managing diarrhea by recognizing signs of diarrhea, implementing anti-diarrheal treatment (e.g., medications, hydration, adjusting anti-diarrheal dosage according to the protocol), and reporting signs and symptoms to investigators.

   Per Health Canada's recommendation, the proposed PM was revised to more effectively communicate the risk and risk mitigation recommendations for treatment-related diarrhea. The key changes included:

   1. addition of the statement "close monitoring and proactive management of diarrhea is essential for successful Giotrif treatment" in the Indications and Clinical Use section;
   2. addition of a detailed description of the diarrhea management protocol employed in the pivotal study in the Warnings and Precautions section;
   3. addition of the recommendation that "prescribers should ensure that patients are well informed of the risk of diarrhea and are able to proactively manage the side effect" and "patients should be provided with contact information of a physician experienced in cancer treatment and seek advice on diarrhea management" and
   4. an revisions to the table that outlines Giotrif dose adjustment recommendations to be consistent with those in the pivotal study.
4. A Risk Management Plan (RMP) for Giotrif was submitted and reviewed by Health Canada. The RMP describes known and potential safety issues, presents the monitoring scheme, and describes measures that will be put in place to minimize risks associated with Giotrif under the authorized use. A sponsor initiated drug-distribution scheme will be assessed by Health Canada as an Annex under the RMP. Health Canada considers that such a scheme may offer additional benefit for managing diarrhea and other Giotirf-related risk.

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