CLINICAL STUDIES

14 Figure 1: Kaplan-Meier Progression-free Survival Curves (Investigator Radiological Review) Figure 2: Kaplan-Meier Investigator-Determined Progression-free Survival Curves Figure 4: Kaplan-Meier Progression-free Survival Curves Figure 3: Kaplan-Meier Progression-free Survival Curves 14.1 Advanced Hormone Receptor-Positive, HER2-Negative Breast Cancer A randomized, double-blind, multicenter study of AFINITOR plus exemestane versus placebo plus exemestane was conducted in 724 postmenopausal women with estrogen receptor-positive, HER2/neu-negative advanced breast cancer with recurrence or progression following prior therapy with letrozole or anastrozole.

Randomization was stratified by documented sensitivity to prior hormonal therapy (yes versus no) and by the presence of visceral metastasis (yes versus no).

Sensitivity to prior hormonal therapy was defined as either (1) documented clinical benefit (complete response [CR], partial response [PR], stable disease ≥ 24 weeks) to at least one prior hormonal therapy in the advanced setting or (2) at least 24 months of adjuvant hormonal therapy prior to recurrence.

Patients were permitted to have received 0-1 prior lines of chemotherapy for advanced disease.

The primary endpoint for the trial was progression-free survival (PFS) evaluated by Response Evaluation Criteria In Solid Tumors (RECIST), based on investigator (local radiology) assessment.

Other endpoints included overall survival (OS), objective response rate (ORR), and safety.

Patients were randomly allocated in a 2:1 ratio to AFINITOR 10 mg/day plus exemestane 25 mg/day (n=485) or to placebo plus exemestane 25 mg/day (n=239).

The two treatment groups were generally balanced with respect to baseline demographics and disease characteristics.

Patients were not permitted to cross over to AFINITOR at the time of disease progression.

The median progression-free survival by investigator assessment at the time of the final PFS analysis was 7.8 and 3.2 months in the AFINITOR and placebo arms, respectively [HR = 0.45 (95% CI: 0.38, 0.54), one-sided log-rank p <0.0001] (see Table 14 and Figure 1).

The results of the PFS analysis based on independent central radiological assessment were consistent with the investigator assessment.

PFS results were also consistent across the subgroups of age, race, presence and extent of visceral metastases, and sensitivity to prior hormonal therapy.

Objective response rate was 12.6% (95% CI: 9.8, 15.9) in the AFINITOR plus exemestane arm versus 1.7% (95% CI: 0.5, 4.2) in the placebo plus exemestane arm.

There were 3 complete responses (0.6%) and 58 partial responses (12.0%) in the AFINITOR plus exemestane arm.

There were no complete responses and 4 partial responses (1.7%) in the placebo plus exemestane arm.

After a median follow-up of 39.3 months, there was no statistically significant difference in OS between the AFINITOR plus exemestane arm and the placebo plus exemestane arm [HR 0.89 (95% CI 0.73, 1.10)].

Table 14: Progression-free Survival Results a Exemestane (25 mg/day) b Hazard ratio is obtained from the stratified Cox proportional-hazards model by sensitivity to prior hormonal therapy and presence of visceral metastasis c p-value is obtained from the one-sided log-rank test stratified by sensitivity to prior hormonal therapy and presence of visceral metastasis d Objective response rate = proportion of patients with CR or PR e not applicable Analysis AFINITOR + exemestanea N = 485 Placebo + exemestanea N = 239 Hazard ratio P-value Median progression-free survival (months, 95% CI) Investigator radiological review 7.8 (6.9 to 8.5) 3.2 (2.8 to 4.1) 0.45b (0.38 to 0.54) <0.0001c Independent radiological review 11.0 (9.7 to 15.0) 4.1 (2.9 to 5.6) 0.38b (0.3 to 0.5) <0.0001c Best overall response (%, 95% CI) Objective response rate (ORR)d 12.6% (9.8 to 15.9) 1.7% (0.5 to 4.2) n/ae Figure 1: Kaplan-Meier Progression-free Survival Curves (Investigator Radiological Review) 14.2 Advanced Neuroendocrine Tumors Locally Advanced or Metastatic Advanced Pancreatic Neuroendocrine Tumors (PNET) A randomized, double-blind, multi-center trial of AFINITOR plus best supportive care (BSC) versus placebo plus BSC was conducted in patients with locally advanced or metastatic advanced pancreatic neuroendocrine tumors (PNET) and disease progression within the prior 12 months.

Patients were stratified by prior cytotoxic chemotherapy (yes versus no) and by WHO performance status (0 versus 1 and 2).

Treatment with somatostatin analogs was allowed as part of BSC.

The primary endpoint for the trial was progression-free survival (PFS) evaluated by RECIST (Response Evaluation Criteria in Solid Tumors).

After documented radiological progression, patients could be unblinded by the investigator; those randomized to placebo were then able to receive open-label AFINITOR.

Other endpoints included safety, objective response rate [ORR (complete response (CR) or partial response (PR)], response duration, and overall survival.

Patients were randomized 1:1 to receive either AFINITOR 10 mg/day (n=207) or placebo (n=203).

Demographics were well balanced (median age 58 years, 55% male, 79% Caucasian).

Of the 203 patients randomized to best supportive care, 172 patients (85%) received AFINITOR following documented radiologic progression.

The trial demonstrated a statistically significant improvement in PFS (median 11.0 months versus 4.6 months), resulting in a 65% risk reduction in investigator-determined PFS (HR 0.35; 95%CI: 0.27 to 0.45; p<0.001) (see Table 15 and Figure 2).

PFS improvement was observed across all patient subgroups, irrespective of prior somatostatin analog use.

The PFS results by investigator radiological review, central radiological review and adjudicated radiological review are shown below in Table 15.

Table 15: Progression-free Survival Results a includes adjudication for discrepant assessments between investigator radiological review and central radiological review Analysis N AFINITOR N=207 Placebo N=203 Hazard Ratio (95%CI) p-value 410 Median progression-free survival (months) (95% CI) Investigator radiological review 11.0 (8.4 to 13.9) 4.6 (3.1 to 5.4) 0.35 (0.27 to 0.45) <0.001 Central radiological review 13.7 (11.2 to 18.8) 5.7 (5.4 to 8.3) 0.38 (0.28 to 0.51) <0.001 Adjudicated radiological reviewa 11.4 (10.8 to 14.8) 5.4 (4.3 to 5.6) 0.34 (0.26 to 0.44) <0.001 Figure 2: Kaplan-Meier Investigator-Determined Progression-free Survival Curves Investigator-determined response rate was 4.8% in the AFINITOR arm and there were no complete responses.

Overall survival was not statistically significantly different between study arms [HR=0.94 (95% CI 0.73 to 1.20); p=0.30].

Unresectable, Locally Advanced or Metastatic, Well-Differentiated, Non-Functional Neuroendocrine Tumors of Gastrointestinal or Lung Origin A randomized, double-blind, multicenter study of AFINITOR plus best supportive care (BSC) versus placebo plus best supportive care was conducted in patients with unresectable, locally advanced or metastatic, well differentiated, non-functional neuroendocrine tumors (NET) of gastrointestinal (excluding pancreatic) or lung origin.

The study required that patients had well-differentiated (low or intermediate grade) histology, no prior or current history of carcinoid symptoms, and evidence of disease progression within 6 months prior to randomization.

Patients were randomized 2:1 to receive either AFINITOR 10 mg/day or placebo, and stratified by prior somatostatin analog (SSA) use (yes versus no), tumor origin and WHO performance status (0 versus 1).

The major efficacy outcome measure was progression-free survival (PFS) based on independent radiological assessment evaluated by RECIST.

Additional efficacy outcome measures were overall survival and overall response rate.

A total of 302 patients were randomized, 205 to the AFINITOR arm and 97 to the placebo arm.

The median age was 63 years (range 22 to 86); 47% were male; 76% were White; 74% had WHO performance status (PS) 0 and 26% had WHO PS 1.

The most common primary sites of tumor were lung (30%), ileum (24%), and rectum (13%).

The study demonstrated a statistically significant improvement in PFS per independent radiological review (see Table 16 and Figure 3).

There was no statistically significant difference in OS at the planned interim analysis.

Table 16: Efficacy Results 1.

Hazard ratio is obtained from the stratified Cox model.

2.

p-value is obtained from the stratified log-rank test.

AFINITOR N=205 Placebo N=97 Progression-Free Survival Number of Events 113 (55%) 65 (67%) Progressive Disease 104 (51%) 60 (62%) Death 9 (4%) 5 (5%) Median PFS in months (95% CI) 11.0 (9.2, 13.3) 3.9 (3.6, 7.4) Hazard Ratio (95%CI)1 0.48 (0.35, 0.67) p-value2 <0.001 Overall Response Rate 2% 1% Figure 3: Kaplan-Meier Progression-free Survival Curves Lack of Efficacy in Locally Advanced or Metastatic Functional Carcinoid Tumors The safety and effectiveness of AFINITOR in patients with locally advanced or metastatic functional carcinoid tumors have not been demonstrated.

In a randomized (1:1), double-blind, multi-center trial in 429 patients with carcinoid tumors, AFINITOR plus depot octreotide (Sandostatin LAR®) was compared to placebo plus depot octreotide.

After documented radiological progression, patients on the placebo arm could receive AFINITOR; of those randomized to placebo, 143 (67%) patients received open-label AFINITOR plus depot octreotide.

The study did not meet its primary efficacy endpoint of a statistically significant improvement in PFS and the final analysis of OS favored the placebo plus depot octreotide arm.

14.3 Advanced Renal Cell Carcinoma An international, multi-center, randomized, double-blind trial comparing AFINITOR 10 mg daily and placebo, both in conjunction with best supportive care, was conducted in patients with metastatic RCC whose disease had progressed despite prior treatment with sunitinib, sorafenib, or both sequentially.

Prior therapy with bevacizumab, interleukin 2, or interferon-α was also permitted.

Randomization was stratified according to prognostic score1 and prior anticancer therapy.

Progression-free survival (PFS), documented using Response Evaluation Criteria in Solid Tumors (RECIST) was assessed via a blinded, independent, central radiologic review.

After documented radiological progression, patients could be unblinded by the investigator: those randomized to placebo were then able to receive open-label AFINITOR 10 mg daily.

In total, 416 patients were randomized 2:1 to receive AFINITOR (n=277) or placebo (n=139).

Demographics were well balanced between the 2 arms (median age 61 years; 77% male, 88% Caucasian, 74% received prior sunitinib or sorafenib, and 26% received both sequentially).

AFINITOR was superior to placebo for PFS (see Table 17 and Figure 4).

The treatment effect was similar across prognostic scores and prior sorafenib and/or sunitinib.

Final overall survival (OS) results yield a hazard ratio of 0.90 (95% CI: 0.71 to 1.14), with no statistically significant difference between the 2 treatment groups.

Planned cross-over from placebo due to disease progression to open label AFINITOR occurred in 111 of the 139 patients (79.9%) and may have confounded the OS benefit.

Table 17: Efficacy Results by Central Radiologic Review a Log-rank test stratified by prognostic score.

b Not applicable.

AFINITOR N=277 Placebo N=139 Hazard R atio (95% CI) p-value a Median P rogression- free S urvival (95% CI) 4.9 months (4.0 to 5.5) 1.9 months (1.8 to 1.9) 0.33 (0.25 to 0.43) <0.0001 Objective R esponse R ate 2% 0% n/a b n/a b Figure 4: Kaplan-Meier Progression-free Survival Curves 14.4 Renal Angiomyolipoma with Tuberous Sclerosis Complex A randomized (2:1), double-blind, placebo-controlled trial of AFINITOR was conducted in 118 patients with renal angiomyolipoma as a feature of TSC (n=113) or sporadic lymphangioleiomyomatosis (n=5).

The key eligibility requirements for this trial were at least one angiomyolipoma of ≥3 cm in longest diameter on CT/MRI based on local radiology assessment, no immediate indication for surgery, and age ≥18 years.

Patients received daily oral AFINITOR 10 mg or matching placebo until disease progression or unacceptable toxicity.

CT or MRI scans for disease assessment were obtained at baseline, 12, 24, and 48 weeks and annually thereafter.

Clinical and photographic assessment of skin lesions were conducted at baseline and every 12 weeks thereafter until treatment discontinuation.

The major efficacy outcome measure was angiomyolipoma response rate based on independent central radiology review, which was defined as a ≥50% reduction in angiomyolipoma volume, absence of new angiomyolipoma lesion ≥1 cm, absence of kidney volume increase ≥20%, and no angiomyolipoma related bleeding of ≥ Grade 2.

Key supportive efficacy outcome measures were time to angiomyolipoma progression and skin lesion response rate.

The primary analyses of efficacy outcome measures were limited to the blinded treatment period and conducted 6 months after the last patient was randomized.

The comparative angiomyolipoma response rate analysis was stratified by use of enzyme-inducing antiepileptic drugs (EIAEDs) at randomization (yes versus no).

Of the 118 patients enrolled, 79 were randomized to AFINITOR and 39 to placebo.

The median age was 31 years (range 18 to 61 years), 34% were male, and 89% were Caucasian.

At baseline, 17% of patients were receiving EIAEDs.

On central radiology review at baseline, 92% of patients had at least 1 angiomyolipoma of ≥3 cm in longest diameter, 29% had angiomyolipomas ≥8 cm, 78% had bilateral angiomyolipomas, and 97% had skin lesions.

The median values for the sum of all target renal angiomyolipoma lesions at baseline were 85 cm3 (range 9 to 1612 cm3) and 120 cm3 (range 3 to 4520 cm3) in the AFINITOR and placebo arms respectively.

Forty-six (39%) patients had prior renal embolization or nephrectomy.

The median duration of follow-up was 8.3 months (range 0.7 to 24.8 months) at the time of the primary analysis.

The renal angiomyolipoma response rate was statistically significantly higher in AFINITOR-treated patients; there were 33 (41.8%) patients with angiomyolipoma responses in the AFINITOR arm as compared to none in the placebo arm.

Results are displayed in Table 18.

The median response duration was 5.3+ months (range 2.3+ to 19.6+ months).

There were 3 patients in the AFINITOR arm and 8 patients in the placebo arm with documented angiomyolipoma progression by central radiologic review (defined as a ≥25% increase from nadir in the sum of angiomyolipoma target lesion volumes to a value greater than baseline, appearance of a new angiomyolipoma ≥1.0 cm in longest diameter, an increase in renal volume ≥ 20% from nadir for either kidney and to a value greater than baseline, or Grade ≥2 angiomyolipoma-related bleeding).

The time to angiomyolipoma progression was statistically significantly longer in the AFINITOR arm (HR 0.08 [95% CI: 0.02, 0.37]; p <0.0001).

Table 18: Angiomyolipoma Response a Per independent central radiology review AFINITOR Placebo p-value N=79 N=39 Primary analysis Angiomyolipoma response ratea – % 41.8 0 <0.0001 95% CI (30.8, 53.4) (0.0, 9.0) Skin lesion response rates were assessed by local investigators for 77 patients in the AFINITOR arm and 37 patients in the placebo arm who presented with skin lesions at study entry.

The skin lesion response rate was statistically significantly higher in the AFINITOR arm (26% versus 0, p=0.0011); all skin lesion responses were partial responses, defined as visual improvement in 50%-99% of all skin lesions durable for at least 8 weeks (Physician’s Global Assessment of Clinical Condition).

Patients randomized to placebo were permitted to receive AFINITOR at the time of angiomyolipoma progression or after the time of the primary analysis.

After the primary analysis, patients treated with AFINITOR underwent additional follow-up CT or MRI scans to assess tumor status until discontinuation of treatment or completion of 4 years of follow-up after the last patient was randomized.

A total of 112 patients (79 randomized to AFINITOR and 33 randomized to placebo) received at least one dose of AFINITOR.

The median duration of AFINITOR treatment was 3.9 years (range: 0.5 months to 5.3 years) and the median duration of follow-up was 3.9 years (range: 0.9 months to 5.4 years).

During the follow-up period after the primary analysis, 32 patients (in addition to the 33 patients identified at the time of the primary analysis) had an angiomyolipoma response based upon independent central radiology review.

Among the 65 responders out of 112 patients, the median time to angiomyolipoma response was 2.9 months (range: 2.6 to 33.8 months).

Sixteen of the 112 patients treated with AFINITOR had angiomyolipoma progression by the end of the follow-up period.

No patient underwent a nephrectomy for angiomyolipoma progression and one patient underwent renal embolization while treated with AFINITOR.

14.5 Subependymal Giant Cell Astrocytoma with Tuberous Sclerosis Complex Study 1 was a randomized (2:1), double-blind, placebo-controlled trial of AFINITOR conducted in 117 pediatric and adult patients with subependymal giant cell astrocytoma (SEGA) and tuberous sclerosis complex (TSC).

Eligible patients had at least one SEGA lesion ≥1.0 cm in longest diameter on MRI based on local radiology assessment and one or more of the following: serial radiological evidence of SEGA growth, a new SEGA lesion ≥1 cm in longest diameter, or new or worsening hydrocephalus.

Patients randomized to the treatment arm received AFINITOR tablets at a starting dose of 4.5 mg/m2 daily, with subsequent dose adjustments as needed to achieve and maintain everolimus trough concentrations of 5 to 15 ng/mL as tolerated.

AFINITOR/matched placebo treatment continued until disease progression or unacceptable toxicity.

MRI scans for disease assessment were obtained at baseline, 12, 24, and 48 weeks, and annually thereafter.

The main efficacy outcome measure was SEGA response rate based on independent central radiology review.

SEGA response was defined as a ≥ 50% reduction in the sum of SEGA volume relative to baseline, in the absence of unequivocal worsening of non-target SEGA lesions, a new SEGA lesion ≥ 1 cm, and new or worsening hydrocephalus.

The primary analysis of SEGA response rate was limited to the blinded treatment period and conducted 6 months after the last patient was randomized.

The analysis of SEGA response rate was stratified by use of enzyme-inducing antiepileptic drugs (EIAEDs) at randomization (yes versus no).

Of the 117 patients enrolled, 78 were randomized to AFINITOR and 39 to placebo.

The median age was 9.5 years (range 0.8 to 26 years; 69% were 3 to < 18 years at enrollment; 17% were <3 years at enrollment), 57% were male, and 93% were Caucasian.

At baseline, 18% of patients were receiving EIAEDs.

Based on central radiology review at baseline, 98% of patients had at least one SEGA lesion ≥1.0 cm in longest diameter, 79% had bilateral SEGAs, 43% had ≥2 target SEGA lesions, 26% had growth in or into the inferior surface of the ventricle, 9% had evidence of growth beyond the subependymal tissue adjacent to the ventricle, and 7% had radiographic evidence of hydrocephalus.

The median values for the sum of all target SEGA lesions at baseline were 1.63 cm3 (range 0.18 to 25.15 cm3) and 1.30 cm3 (range 0.32 to 9.75 cm3) in the AFINITOR and placebo arms respectively.

Eight (7%) patients had prior SEGA-related surgery.

The median duration of follow-up was 8.4 months (range 4.6 to 17.2 months) at the time of primary analysis.

The SEGA response rate was statistically significantly higher in AFINITOR-treated patients.

There were 27 (35%) patients with SEGA responses in the AFINITOR arm and no SEGA responses in the placebo arm.

Results are displayed in Table 19.

At the time of the primary analysis, all SEGA responses were ongoing and the median duration of response was 5.3 months (range 2.1 to 8.4 months).

With a median follow-up of 8.4 months, SEGA progression was detected in 6 of 39 (15.4%) patients randomized to receive placebo and none of the 78 patients randomized to receive AFINITOR.

No patient in either treatment arm required surgical intervention.

Table 19: SEGA Response a Per independent central radiology review AFINITOR Placebo p-value N=78 N=39 Primary analysis SEGA response ratea – (%) 35 0 <0.0001 95% CI 24, 46 0, 9 Patients randomized to placebo were permitted to receive AFINITOR at the time of SEGA progression or after the primary analysis, whichever occurred first.

After the primary analysis, patients treated with AFINITOR underwent additional follow-up MRI scans to assess tumor status until discontinuation of treatment or completion of 4 years of follow-up after the last patient was randomized.

A total of 111 patients (78 patients randomized to AFINITOR and 33 patients randomized to placebo) received at least one dose of AFINITOR.

Median duration of AFINITOR treatment and follow-up was 3.9 years (range: 0.2 to 4.9 years).

By four years after the last patient was enrolled, a total of 64 of the 111 patients treated with AFINITOR had a ≥50% reduction in SEGA volume relative to baseline, including 27 patients identified at the time of the primary analysis and 37 patients with a SEGA response after the primary analysis.

The median time to SEGA response was 5.3 months (range: 2.5 to 33.1 months).

Thirteen of the 111 patients treated with AFINITOR had documented disease progression by the end of the follow-up period and no patient required surgical intervention for SEGA during the course of the study.

Study 2 was an open-label, single-arm trial conducted to evaluate the safety and antitumor activity of AFINITOR 3.0 mg/m2/orally once daily in patients with SEGA and TSC.

Serial radiological evidence of SEGA growth was required for entry.

Tumor assessments were performed every 6 months for 60 months after the last patient was enrolled or disease progression, whichever occurred earlier.

The major efficacy outcome measure was the reduction in volume of the largest SEGA lesion with 6 months of treatment, as assessed via independent central radiology review.

Progression was defined as an increase in volume of the largest SEGA lesion over baseline that was ≥25% over the nadir observed on study.

Study 2 enrolled 28 patients who received AFINITOR for a median duration of 5.7 years (range: 5 months to 6.9 years); 23 of 28 patients (82%) remained on AFINITOR for at least 5 years.

Across the study population, the median age was 11 years (range 3-34), 61% male, 86% Caucasian.

At the primary analysis, 9 of 28 patients [32% (95% CI: 16% to 52%)] had an objective response at 6 months, defined as at least a 50% decrease in volume of the largest SEGA lesion.

At the completion of the study, the median duration of durable response was 12 months (range 3 months to 6.3 years).

By 60 months after the last patient was enrolled, 11% of patients (3/28) had documented disease progression.

No patient developed a new SEGA lesion while on AFINITOR.

Nine additional patients were identified as having a >50% volumetric reduction in their largest SEGA lesion between 1 to 4 years after initiating AFINITOR including 3 patients who had surgical resection with subsequent regrowth prior to receiving AFINITOR.