a phase ii, multicenter, open-label study of egf816 in

Novartis Confidential AACR2020 10-Mar-2021 (17:03) EGF816X2201C

Clinical Development

EGF816, INC280, Nivolumab

CEGF816X2201C / NCT02323126

A phase II, multicenter, open-label study of EGF816 in combination with Nivolumab in adult patients with EGFR

mutated non-small cell lung cancer and of INC280 in combination with Nivolumab in adult patients with cMet

positive non-small cell lung cancer

Statistical Analysis Plan for WCLC 2021

Author(s): Trial Statistician

Document type: SAP Documentation

Document status: Final

Release date: 03-Aug -2020

Number of pages: 32

Property of Novartis Confidential

May not be used, divulged, published or otherwise disclosed without the consent of Novartis

Novartis Confidential AACR2020 10-Mar-2021 (17:03) EGF816X2201C Change control

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Novartis Confidential AACR2020 10-Mar-2021 (17:03) EGF816X2201C Table of contents 1 General guidance ................................................................................................................. 4

1.1 Analysis sets ....................................................................................................................................... 4 1.2 Group labels and ordering ................................................................................................................... 5

2 Outputs ................................................................................................................................ 6 2. General specification ........................................................................................................................... 6 2.2 Naming convention ............................................................................................................................. 6 2.3 Data panels ....................................................................................................................................... 6 2.4 Data from 3rd party vendor .................................................................................................................. 7 2.5 Specific output shells .......................................................................................................................... 7 Table 10-1 Patient disposition (Full analysis set) ........................................................................................... 7 Figure 11-3 Waterfall plot for best percentage change from baseline in target lesions and best overall response for each group (Full analysis set) ..................................................................................................... 8 Figure 11-4 Kaplan-Meier plot of progression-free survival by group (Full analysis set) .............................. 9 Table 11-2 Demographics and baseline characteristics (Full analysis set) ................................................... 10 Table 11-7 Primary PK parameters for INC280 (INC-FPAS) ...................................................................... 12 Table 11-8 Analysis of PFS by group using Kaplan-Meier method (Full analysis set) ................................ 13 Table 11-9 Analysis of overall survival by group using Kaplan-Meier method (Full analysis set) .............. 13 Table 12-3 Overview of adverse events (Safety set) ..................................................................................... 14 Table 12-4 Adverse events by preferred term (Safety set) ............................................................................ 15 Table 12-5 Serious adverse events by preferred term (Safety set) ................................................................ 15 Table 12-7 Adverse events suspected to study treatment related by preferred term (Safety set) .................. 16 Table 12-8 Serious adverse events suspected to study treatment related by preferred term (Safety set) ...... 17 Figure 14.2-2 Kaplan-Meier plot of overall survival per investigator (Full analysis set) ............................. 18 Table 14.2-1 Best overall response (Full analysis set) .................................................................................. 19 Table 14.2-2 Descriptive summary of duration of response (CR+PR) (Full analysis set) ............................ 20 Figure 14.2-4 Arithmetic and geometric mean profiles for INC280 (INC-FPAS) ........................................ 21 Figure 14.2-8.1 Box plot of HGF at baseline vs best overall response (Full analysis set) ............................ 24 Figure 14.2-8.2 Box plot of change from baseline in HGF at Cycle 3 Day 1 vs best overall response (Full analysis set) ..................................................................................................................................... 24 Listing 14.3.2-1 Deaths (Safety set) .............................................................................................................. 25 Listing 16.2.3-1 Analysis sets (Full analysis set) .......................................................................................... 25 Listing 16.2.5-2 Dose administration record for INC280 (Full analysis set) ................................................ 26 Listing 16.2.5-3 Dose administration record for Nivolumab (Full analysis set) ........................................... 27 Listing 16.2.6-1 Overall response per patient by assessment cycle and group (Full analysis set) ................ 28 Listing 16.2.6-2 Lesions evaluations (by RECIST criteria) (Full analysis set) ............................................. 29 Listing 16.2.6-4 Time to progression and death per patient by group (Full analysis set) ............................. 30 Listing 16.2.7-1 Adverse events (Safety set) ................................................................................................ 31 Listing 16.2.8-8 MET amplification, mutation and IHC expression status by cohort (Full analysis set) ..... 32

Novartis Confidential AACR2020 10-Mar-2021 (17:03) EGF816X2201C 1 General guidance This statistical analysis plan (SAP) serves as the reference for efficacy analysis tables, figures, and listings (TFL) required in support of the WCLC submission for EGF816X2201C. It has been developed using Clinical Trial Protocol version v08 dated 12-Mar-2020 . Data cut-off date: 03-Aug-2020. Data snapshot: 31-Aug-2020

1.1 Analysis sets Only protocol-defined Group 2 patients are included in this analysis. The following analysis sets will be used for this analysis.

Full Analysis Set

The Full Analysis Set (FAS) comprises all patients who have received at least one dose of INC280 or Nivolumab. Patients will be analyzed according to the planned treatment they have been assigned to. The FAS will be used for all listing of raw data.

Safety Set

The Safety Set includes all patients who received at least one dose of INC280 or Nivolumab and have at least one valid post-screening/post-baseline safety assessment. The statement that a patient had no AEs (on the AE eCRF) constitutes a valid safety assessment. Patients will be analyzed according to the study treatment (regimen) they actually received, where treatment actually received is defined as: • The treatment assigned if it was received at least once, or • If the assigned treatment was never received, then the first treatment received when starting

therapy with study treatment will be used for classification The safety set will be the primary population for all safety related endpoints.

Pharmacokinetic Analysis Set (PAS)

The INC280 PAS includes two sets, the INC280 full pharmacokinetic analysis set (INC-FPAS) which will be used for NCA analysis and INC280 pharmacokinetic analysis set (INC-PAS). The INC-FPAS includes all subjects who have provided an INC280 evaluable PK profile on

cycle 1 day 15 (only applicable to subjects with extensive PK sampling in the safety monitoring cohort). An INC280 PK profile is considered evaluable if all of the following conditions are satisfied:

• Subject has received one dose of the planned INC280 treatment • Subject has provided at least one valid primary PK parameter (AUClast, AUCtau, Cmax,

Tmax ) • Subjects did not vomit within 4 hours after the dosing of INC280

Novartis Confidential AACR2020 10-Mar-2021 (17:03) EGF816X2201C The INC-PAS includes all subjects who have provided at least one evaluable INC280 PK

concentration. For an INC280 PK concentration to be evaluable, a subject must: • Have taken the planned dose of INC280 prior to sampling • For pre-dose samples, do not vomit within 4 hours after the dosing of INC280 prior to

sampling • For post-dose samples, do not vomit within 4 hours after the dosing of INC280 • For pre-dose sample, have the sample collected before the next dose administration and 9-15 hours after the last dose administration. The NIVO-PAS includes all subjects who have provided at least one evaluable Nivolumab PK

concentration. For a Nivolumab PK concentration to be evaluable, a subject must: • Have received one of the planned doses (complete infusion) of Nivolumab prior to

sampling • For pre-dose samples, have the sample collected before the next dose administration

Subgroup of interest

The following two subgroups in Group 2 will be considered.

• Group 2A (cMet high): if any one of the following criteria is satisfied:

o IHC score = 3+ in at least 50% of tumor cells (regardless of gene copy number (GCN))

o IHC score = 2+ in at least 50% of tumor cells and GCN>=5 o cMet exon 14 activating mutation positive

• Group 2B (cMet low): if negative or unknown for cMet exon 14 activating mutation AND any one of the following criteria is satisfied

o IHC score = 2+ in at least 50% of tumor cells and GCN < 5 o IHC score = 2+ in less than 50% of tumor cells (regardless of GCN) o IHC score = 0 or 1+ (regardless of GCN)

1.2 Group labels and ordering Group 2 consists of patients from both Group 2A and Group 2B receiving the same study treatment. However, the degree of molecular aberration differs between two sub-groups, therefore, analysis is performed separately for two sub-groups. . For analyses of safety and pharmacokinetics, additional information with Group 2A and Group 2B in Group 2 pooled will also be presented. The following treatment group label will be used for all tables, listings and figures:

• Group label


Group 2A (Nivolumab 3mg/kg + INC280 400 mg bid)

Group 2B (Nivolumab 3mg/kg + INC280 400 mg bid)

Group 2 (Nivolumab 3mg/kg + INC280 400 mg bid)

2 Outputs

2.1 General specification The output shells are based on current Oncology Standard Tables, Listings, and Figures, if not otherwise specified. In case no data are to be reported then an “empty” output should be created, i.e. with a line stating “There were no observations which met the report criteria”. Programming specifications: Tumor response will be determined locally according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (see Protocol Appendix 4). The local investigator’s assessment will be used for efficacy analyses.

2.2 Naming convention Following header should be presented in the upper left corner of outputs "CEGF816X2201C – WCLC2021 (Group 2 only) - Date of cutoff: 03Aug2020". In general the output names will consist of the (abbreviated) study number, analysis type and the output number, for example “X2201C_WCLC2021_T10_01”.

2.3 Data panels • Adverse events (AE) • Antineoplastic therapy since discontinuation of study treatment - medication,

radiotherapy, surgery (ZT, ZB, ZP) • Biomarker results (B1) • Blood collection for PK (ZJ) • Death (ZD) • Demography (DM) • Diagnosis and extent of cancer (ZT,FAZT,ZC) • Disposition and treatment assignment (DS) • Dose administration record (ZQ) • ECOG (QS) • Lab assessment (LB) • PK concentration (ZK) • Prior antineoplastic therapy – medication, radiotherapy, surgery (ZT, ZB, ZP) • Protocol deviation (DV)

Novartis Confidential AACR2020 10-Mar-2021 (17:03) EGF816X2201C • RECIST/IRRC (ZI, ZR) • Subject element (SE) • Subject visit (SV) • Survival (CM) • Treatment exposure (EX)

2.4 Data from 3rd party vendor • • • Biomarker data (cMET IHC and FISH) from Navigate • • PK sample analysis data for INC280 from Wuxi • PK sample analysis data for Nivolumab from PPD

2.5 Specific output shells

Table 10-1 Patient disposition (Full analysis set) Group 2A

N=xxx n (%)

Group 2B N=xxx n (%)

Group 2 N=xxx n (%)

Subjects treated Treatment ongoing * xx (xx.x) xx (xx.x) xx (xx.x) End of treatment xx (xx.x) xx (xx.x) xx (xx.x)

Primary reason for end of treatment Reason 1 xx (xx.x) xx (xx.x) xx (xx.x) Reason 2 xx (xx.x) xx (xx.x) xx (xx.x)

Reason 3 xx (xx.x) xx (xx.x) xx (xx.x)

* Ongoing at the time of the data cut-off date YYYY-MM-DD Source: Listing 16.2.1-1.1 Programming Note 1. Adapt disposition table to cover all study phases / epochs (e.g. extension phase / double -blind phase /open-label phase). For complex

study designs, the table may be split to better display the subject flow for some epochs / study phases. Note number of subjects ongoing in overall survival follow-up do not need to be included in the disposition table.

2. Adapt the rows to ensure that all subjects in the FAS are fully accounted for (i.e. completed/discontinued/crossed over/ongoing) for all study phases / epochs.

3. Sort reasons for not being treated and discontinuation by descending frequency in Investigational drug column of highest relevance and subgroup (e.g. subgroup with highest N).

4. Only present non-zero rows (in-text and post-text).

Note that Group 2A and Group 2B were coded as trt01p= Group2’ and trt01p= Group3’ in clinical database, respectively (the same hereinafter).

Novartis Confidential AACR2020 10-Mar-2021 (17:03) EGF816X2201C Figure 11-3 Waterfall plot for best percentage change from baseline in target lesions and best overall response for each group (Full analysis set)

Patients for whom the best percentage change from baseline in target lesions was not available and patients for whom the best percentage change from baseline in target lesions was contradicted by overall lesion response = UNK were excluded. n=number of patients included Source: Listings 16.2.6-1, 16.2.6-2 Programming Note 1. Display Group 2A in the left plot, and Group 2B in the right plot 2. Use confirmed BOR by investigator. 3. Display both FISH gene copy number and BOR as two rows on the top of the bars 4. Horizontal reference lines for 30% reduction and 20% increase will be displayed 5. Add number of patients (i.e., n=xx) for each group in the label 6. Set subject whose percentage change is higher than 100 to a value specified by the programmer (default = 100), a star will then be

displayed for those subjects and respective footnote will be added 7. If applicable, display the patients with the best percentage change from baseline in target lesions contradicted by overall lesion

response=PD as “*”. 8. Flag patients having MET exon 14 skipping mutation, 9. Flag patients having MET H1094Y point mutation

Novartis Confidential AACR2020 10-Mar-2021 (17:03) EGF816X2201C Figure 11-4 Kaplan-Meier plot of progression-free survival by group (Full analysis set)

Source: Listing 16.2.6-4 Programming Note Also display 95% CI for median PFS as well as the estimated PFS rate at 6 months and its 95% CI.

Novartis Confidential AACR2020 10-Mar-2021 (17:03) EGF816X2201C Table 11-2 Demographics and baseline characteristics (Full analysis set) Demographic variable

Group 2A N=xxx

Group 2B N=xxx

Group 2 N=xxx

Age (years) n xxx xxx xxx Mean (SD) xx.x (x.xx) xx.x (x.xx) xx.x (x.xx) Median xx.x xx.x xx.x Min-Max xx-xx xx-xx xx-xx

Age category-n (%) 18-<65 years xx (xx.x) xx (xx.x) xx (xx.x) 65-<85 ≥85 years xx (xx.x) xx (xx.x) xx (xx.x) Missing xx (xx.x) xx (xx.x) xx (xx.x)

Sex-n (%) Female xx (xx.x) xx (xx.x) xx (xx.x) Male xx (xx.x) xx (xx.x) xx (xx.x) Missing xx (xx.x) xx (xx.x) xx (xx.x)

Race-n (%) Asian xx (xx.x) xx (xx.x) xx (xx.x) Caucasian xx (xx.x) xx (xx.x) xx (xx.x) Other xx (xx.x) xx (xx.x) xx (xx.x)

Weight (kg) n xxx xxx Xxx Mean (SD) xx.x (x.xx) xx.x (x.xx) xx.x (x.xx) Median xx.x xx.x xx.x Min-Max xx.x-xx.x xx.x-xx.x xx.x-xx.x

ECOG performance status-n (%) 0 xx (xx.x) xx (xx.x) xx (xx.x) 1 xx (xx.x) xx (xx.x) xx (xx.x) 2 xx (xx.x) xx (xx.x) xx (xx.x) 3 xx (xx.x) xx (xx.x) xx (xx.x) 4 xx (xx.x) xx (xx.x) xx (xx.x) Missing xx (xx.x) xx (xx.x) xx (xx.x)

Smoking history-n (%) Never smoked xx (xx.x) xx (xx.x) xx (xx.x) Current or former smoker xx (xx.x) xx (xx.x) xx (xx.x) Missing xx (xx.x) xx (xx.x) xx (xx.x)

Disease stage-n (%) IIIA-C xx (xx.x) xx (xx.x) xx (xx.x) IV xx (xx.x) xx (xx.x) xx (xx.x)


Missing xx (xx.x) xx (xx.x) xx (xx.x) Predominant histology/cytology-n (%)

Adenocarcinoma xx (xx.x) xx (xx.x) xx (xx.x) Squamous cell carcinoma xx (xx.x) xx (xx.x) xx (xx.x)

Other xx (xx.x) xx (xx.x) xx (xx.x) Missing xx (xx.x) xx (xx.x) xx (xx.x)

Number of prior lines-n (%) 1 xx (xx.x) xx (xx.x) xx (xx.x) 2 xx (xx.x) xx (xx.x) xx (xx.x)

≥3 xx (xx.x) xx (xx.x) xx (xx.x)

Missing

IHC score-n (%) 0 xx (xx.x) xx (xx.x) xx (xx.x) 1+ xx (xx.x) xx (xx.x) xx (xx.x)

2+ xx (xx.x) xx (xx.x) xx (xx.x)

3+ xx (xx.x) xx (xx.x) xx (xx.x)

Missing xx (xx.x) xx (xx.x) xx (xx.x)

Fish gene copy number-n (%) <4 xx (xx.x) xx (xx.x) xx (xx.x) [4, 6) xx (xx.x) xx (xx.x) xx (xx.x)

[6, 10) xx (xx.x) xx (xx.x) xx (xx.x)

≥10 xx (xx.x) xx (xx.x) xx (xx.x)

Missing xx (xx.x) xx (xx.x) xx (xx.x)

PD-L1 expression-n (%) 0 xx (xx.x) xx (xx.x) xx (xx.x) (0, 50%) xx (xx.x) xx (xx.x) xx (xx.x) [50%-100%] xx (xx.x) xx (xx.x) xx (xx.x) Missing xx (xx.x) xx (xx.x) xx (xx.x)

ECOG performance status: 0 - Fully active, able to carry on all pre-disease performance without restriction; 1 - Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work; 2 - Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more than 50% of waking hours; 3 Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours; 4 Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair.

Source: Listing 16.2.4-1

Programming Note

1. Each therapeutic regimen should be counted as one prior line. In addition, adjuvant systematic therapies will be count as one prior line of treatment if completed within 12 months prior to study treatment.

2. Derivation of ventana score for IHC (b1method='IMMUNOHISTOCHEMISTRY' and b1test in ("PERCENT HIGH STAINING","PERCENT MEDIUM STAINING","PERCENT LOW STAINING") for H, M and L, respectively)

if H >= 50 then do; ventana = '3+'; end; else if H+M >= 50 then do;


ventana = '2+'; end; else if L+M+H >= 50 then do; ventana = '1+'; end; else do; ventana = '0'; end;

Table 11-7 Primary PK parameters for INC280 (INC-FPAS) Group 2A Group 2B Group2 Parameter Statistics N=xx N=xx N=xx

Parameter 1 (unit) n xx xx xx

Mean (SD) xx.x (xx.x) xx.x (xx.x) xx.x (xx.x)

CV% xx.x xx.x xx.x

Geo-mean xx.x xx.x xx.x

Geo-CV% xx.x xx.x xx.x

Median xx.x xx.x xx.x

Min-Max xx.x-xx.x xx.x-xx.x xx.x-xx.x

Parameter 2 (unit) Repeat

...

Tmax (hr) (if presented) Repeat xx xx xx

N/A N/A N/A

N/A N/A N/A

N/A N/A N/A

N/A N/A N/A

xx.x xx.x xx.x

xx.x-xx.x xx.x-xx.x xx.x-xx.x

n = number of subjects with corresponding evaluable PK parameters. Programming Note

• Only patients in safety monitoring cohorts will have PK parameters.

• Follow specifications for Significant digits for reporting PK data’.

• Cycle day C1D15.


• Primary PK parameters are AUClast, AUCtau, Cmax, and Tmax.

Table 11-8 Analysis of PFS by group using Kaplan-Meier method (Full analysis set) Group 2A Group 2B N=xx N=xx

No. of PFS events xx (xx.x %) xx (xx.x %) Progression xx (xx.x %) xx (xx.x %) Death xx (xx.x %) xx (xx.x %) No. of censored

Kaplan-Meier estimates (%) PFS rate [95% CI] at:

xx (xx.x %) xx (xx.x %)

3 months xx.x [xx, xx] xx.x [xx, xx] 6 months xx.x [xx, xx] xx.x [xx, xx] 9 months xx.x [xx, xx] xx.x [xx, xx] 12 months xx.x [xx, xx] xx.x [xx, xx] 25th percentile for PFS [95% CI] xx [xx, xx] xx [xx, xx] Median PFS [95% CI] xx [xx, xx] xx [xx, xx] 75th percentile for PFS [95% CI] xx [xx, xx] xx [xx, xx]

• Source: Listing 16.2.6-4 • Programming Note • Reproduce the table for Per-protocol set (PPS) if PPS is different from FAS.

Table 11-9 Analysis of overall survival by group using Kaplan-Meier method (Full analysis set) Group 2A Group 2B N=xx N=xx

No. of PFS events xx (xx.x %) xx (xx.x %) Progression xx (xx.x %) xx (xx.x %) Death xx (xx.x %) xx (xx.x %) No. of censored

Kaplan-Meier estimates (%) OS rate [95% CI] at:

xx (xx.x %) xx (xx.x %)

3 months xx.x [xx, xx] xx.x [xx, xx] 6 months xx.x [xx, xx] xx.x [xx, xx] 9 months xx.x [xx, xx] xx.x [xx, xx] 12 months xx.x [xx, xx] xx.x [xx, xx] 25th percentile for OS [95% CI] xx [xx, xx] xx [xx, xx] Median OS [95% CI] xx [xx, xx] xx [xx, xx] 75th percentile for OS [95% CI] xx [xx, xx] xx [xx, xx]

• Source: Listing 16.2.6-4 • Programming Note • Reproduce the table for Per-protocol set (PPS) if PPS is different from FAS.

Novartis Confidential AACR2020 10-Mar-2021 (17:03) EGF816X2201C Table 12-3 Overview of adverse events (Safety set)

Group 2A

N=xx Group 2B

N=xx Group 2

N=xx

Category

All grades n (%)

Grade 3/4

n (%)

All grades n (%)

Grade 3/4

n (%)

All grades n (%)

Grade 3/4

n (%) Adverse events xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x)

Treatment-related xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) SAEs xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x)

Treatment-related xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) Fatal SAEs xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x)

Treatment-related xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) AEs leading to study treatment discontinuation

xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x)

Treatment-related xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) AEs leading to dose adjustment/interruption xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x)

AEs requiring additional therapy


Numbers (n) represent counts of subjects. A subject with multiple severity grades for an AE is only counted under the maximum grade. MedDRA version <xx.x>, CTCAE version <x.xx>. Source: Listing 16.2.7-1

Programming Note 1. Overview table providing high-level overview from several different AE tables. 2. Study treatment refers to the combination therapy. 3. The categories presented in this table should correspond to the types of AE tables that have been generated for the study (i.e. AEs, SAEs,

AEs leading to discontinuation….) 4. Include only on-treatment events (as defined in SAP). ’All grades’ includes any AEs with missing grade.


Table 12-4 Adverse events by preferred term (Safety set) Group 2A Group 2B Group 2

_____N=xx_____ _____N=xx_____ _____N=xx_____

Preferred term All grades

n (%) Grade 3/4

n (%) All grades

n (%) Grade3/4

n (%) All grades

n (%) Grade 3/4

n (%) Number of subjects with at least one event


Vomiting xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) Diarrhoea xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) Oedema peripheral xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) Anaemia xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) Fatigue xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) etc. Numbers (n) represent counts of subjects. A subject with multiple severity grades for an AE is only counted under the maximum grade. MedDRA version <xx.x>, CTCAE version <x.xx>. Source: Listing 16.2.7-1

Programming Note

1. Sort by descending frequency in Investigational drug column of highest relevance and subgroup (e.g. subgroup with highest N). 2. Include only on-treatment events (as defined in SAP). ’All grades’ includes any AEs with missing grade.

Table 12-5 Serious adverse events by preferred term (Safety set) Group 2A Group 2B Group 2

N=xx N=xx N=xx


n (%) Grade 3/4

n (%) All grades

n (%) Grade 3/4

n (%) All grades

n (%) Grade 3/4

n (%)

Number of subjects with at least one event


Fatigue xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) Nausea xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x)


Anaemia xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) Diarrhoea xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) Vomiting xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) Constipation xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) Pyrexia xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) Urinary tract infection xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) Injection site reaction xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) Thrombocytopenia xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) Anorexia xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) Dyspnoea xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) Stomatitis xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) Numbers (n) represent counts of subjects. A subject with multiple severity grades for an AE is only counted under the maximum grade. MedDRA version <xx.x>, CTCAE version <x.xx>. Source: Listing 16.2.7-1

Programming Note


Table 12-7 Adverse events suspected to study treatment related by preferred term (Safety set) Group 2A Group 2B Group 2

N=xx N=xx N=xx


n (%) Grade 3/4

n (%) All grades

n (%) Grade 3/4

n (%) All grades

n (%) Grade 3/4

n (%) Number of subjects with at least one event


Fatigue xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) Nausea xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) Anaemia xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) Diarrhoea xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) Vomiting xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x)


Constipation xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) Pyrexia xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) Urinary tract infection xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) Injection site reaction xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) Thrombocytopenia xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) Anorexia xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) Dyspnoea xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) Stomatitis xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) xx (xx.x) Numbers (n) represent counts of subjects. A subject with multiple severity grades for an AE is only counted under the maximum grade. MedDRA version <xx.x>, CTCAE version <x.xx>. Source: Listing 16.2.7-1

Programming Note


Table 12-8 Serious adverse events suspected to study treatment related by preferred term (Safety set) Use the same shell as Table 12-7.


Figure 14.2-2 Kaplan-Meier plot of overall survival per investigator (Full analysis set)

Source: Listing 16.2.6-4 Programming Note Also display the 95% CI for median PFS as well as the estimated PFS at 6 months and its 95% CI.


Table 14.2-1 Best overall response (Full analysis set)

Group 2A

N=xx Group 2B

N=xx Group 2 N=xx

n (%) <95% CI> n (%) <95% CI> n (%) <95% CI>

Best overall response

Complete Response (CR) xx (xx.x) xx (xx.x) xx (xx.x)

Partial Response (PR) xx (xx.x) xx (xx.x) xx (xx.x)

<Non-CR/Non-PD> xx (xx.x) xx (xx.x) xx (xx.x)

Stable Disease (SD) xx (xx.x) xx (xx.x) xx (xx.x)

Progressive Disease (PD) xx (xx.x) xx (xx.x) xx (xx.x)

Unknown (UNK) xx (xx.x) xx (xx.x) xx (xx.x)

<Not Assessed> xx (xx.x) xx (xx.x) xx (xx.x)

Overall Response Rate (ORR: CR+PR)

xx (xx.x) (xx.x, xx.x) xx (xx.x) (xx.x, xx.x) xx (xx.x) (xx.x, xx.x)

<Disease Control Rate (DCR: CR+PR+SD<+Non-CR/Non-PD>)>

xx (xx.x) (xx.x, xx.x) xx (xx.x) (xx.x, xx.x) xx (xx.x) (xx.x, xx.x)

N: The total number of subjects in the group. It is the denominator for percentage (%) calculation. n: Number of <patient>s who are at the corresponding category. <The 95% CI for the frequency distribution of each variable were computed using exact method.>


Table 14.2-2 Descriptive summary of duration of response (CR+PR) (Full analysis set) Group 2A

N=xx Group 2B N=xx

Group 2 N=xx

Number of responders, n(%) xx (xx.x) xx (xx.x) xx (xx.x)

Duration of response (months), n(%)*

>=3 <6 months xx (xx.x) xx (xx.x) xx (xx.x)




<3-month interval> xx (xx.x) xx (xx.x) xx (xx.x)

Duration of response (months)

n Mean SD Median

xx xx.x xx.xx xx.x

xx xx.x xx.xx xx.x

xx xx.x xx.xx xx.x

Min Max

xx.x xx.x

xx.x xx.x

xx.x xx.x

N: The total number of subjects in the group. It is the denominator for percentage (%) calculation.

n: Number of <patient>s who are at the corresponding category.

* The total number of responders is the denominator for percentage (%) calculation.


Figure 14.2-4 Arithmetic and geometric mean profiles for INC280 (INC-FPAS) Linear View

Programming Note

NOVDD Excluded concentrations should not be presented; NCDS Concentrations excluded via CNINCFLN should not be presented.

Present by actual treatment.

Dots are medians at each timepoint and are optional, provide legends in figure if used and ensure median is based on Safety set. Adjust title if “median” is NOT presented.

Provide semi-log plot as default, but linear plot may also be used instead.

Y-axis label <matrix, analyte> concentration (units); time units on X-axis may be in days for drugs with a long half-life.


Table 14.2-7.1 Nivolumab serum concentrations (µg/mL) (NIVO-PAS)

Visit Scheduled sampling timepoint Statistics

Group 1 N=xx

Group 2A N=xx

Group 2B N=xx

Group 2 N=xx

Cycle 1 Day 1 0 hr (pre-dose) n xx xx xx xx m xx xx xx xx

Mean (SD) xx.x (xx.x) xx.x (xx.x) xx.x (xx.x) xx.x (xx.x)

CV% xx.x xx.x xx.x xx.x

Geo-mean xx.x xx.x xx.x xx.x

Geo-CV% xx.x xx.x xx.x xx.x

Median xx.x xx.x xx.x xx.x

Min-Max xx.x-xx.x xx.x-xx.x xx.x-xx.x xx.x-xx.x

0.5 hr

...

Repeat

Cycle 1 Day 15 ...

n = number of subjects with evaluable values, m = number of non-zero concentrations. Below the limit of quantitation (BLQ) values (< xx ng/mL) have been set to zero. Zero concentrations are considered as missing in Geo-mean and Geo-CV% calculations.

Programming Note: • Follow specifications for ‘Significant digits for reporting PK data’. • ‘Visit’ column is optional and depends on the design. • PK sampling timepoints: 0hr of C1D1, C1D15, C2D1, C4D1, C8D1, every 8th cycle after C8D1 untill discontinuation of study treatment, 2 follow-up visits up to 100 days from end of

treatment.


Table 14.2-7.2 INC280 serum concentrations (ng/mL) (INC-PAS)

Visit Scheduled sampling timepoint Statistics

Group 1 N=xx

Group 2A N=xx

Group 2B N=xx

Group 2 N=xx

Cycle 1 Day 1 0 hr (pre-dose) n xx xx xx xx m xx xx xx xx

Mean (SD) xx.x (xx.x) xx.x (xx.x) xx.x (xx.x) xx.x (xx.x)

CV% xx.x xx.x xx.x xx.x

Geo-mean xx.x xx.x xx.x xx.x

Geo-CV% xx.x xx.x xx.x xx.x

Median xx.x xx.x xx.x xx.x

Min-Max xx.x-xx.x xx.x-xx.x xx.x-xx.x xx.x-xx.x

0.5 hr

...

Repeat

Cycle 1 Day 15 ...

n = number of subjects with evaluable values, m = number of non-zero concentrations. Below the limit of quantitation (BLQ) values (< xx ng/mL) have been set to zero. Zero concentrations are considered as missing in Geo-mean and Geo-CV% calculations. Programming Note: • Follow specifications for ‘Significant digits for reporting PK data’. • ‘Visit’ column is optional and depends on the design. • PK sampling timepoints: 0,1,3,6,8hr of C1D15, 0hr of C2D1, C4D1, C6D1, C8D1.


Figure 14.2-8.1 Box plot of HGF at baseline vs best overall response (Full analysis set)

Group: xxxxx

Note: whiskers extend to the most extreme points with 1.5*(interquartile range) from the box Programming Note: BOR categories: CR+PR, SD, PD

Figure 14.2-8.2 Box plot of change from baseline in HGF at Cycle 3 Day 1 vs best overall response (Full analysis set) Same output shells as Figure 14.2-8.2


Listing 14.3.2-1 Deaths (Safety set)

Group: xxxxx Country/ Age/ Date of Date of Number of

Subject identifier

Sex/ last dose/ Race Study day

death/ Study day

days since last dose

Primary reason reported/ Death due to Preferred term study indication

xxx/xxxxxxx xx/x/xx YYYY-MM-DD/xx YYYY-MM-DD/xx* xx HEAD TRAUMA AND CHEST TRAUMA / No Injury NOS

xxx/xxxxxxx xx/x/xx YYYY-MM-DD/xx YYYY-MM-DD/xx xx XXXXXXXXXXXXXXXXXXXXXXXXX / Yes xxxxxxxxxxxxxxxxxxxxxxxx

* More than <100> days after last study treatment. MedDRA version <xx.x>.

Programming Note: Include all deaths; flag those that occurred more than <100> days after last treatment, as defined in the SAP.

Listing 16.2.3-1 Analysis sets (Full analysis set) Group: xxxxx Country/ Age/

Subject identifier

Sex/ Race

Full analysis set

Safety set

Per-protocol set

xxx/xxxxxxx xx/x/xx Yes Yes Yes xxx/xxxxxxx xx/x/xx Yes Yes Yes xxx/xxxxxxx xx/x/xx Yes Yes No xxx/xxxxxxx xx/x/xx No Yes Yes xxx/xxxxxxx xx/x/xx No No No

Programming Note 1. Groups include Group 2A or Group 2B 2. Please refer to the CSR SAP for definitions of the analysis sets.


Listing 16.2.5-2 Dose administration record for INC280 (Full analysis set) Group: xxxxx, <study drug: xxxxx>

xxx/xxxxxxx xx/x/xx xxx/xxx xxx xxx None YYYY-MM-DD/x/x YYYY-MM-DD/x/x xx

xxx/xxx xxx xxx Change x YYYY-MM-DD/x/x YYYY-MM-DD/x/x xx

xxx/xxx xxx xxx Interr. x YYYY-MM-DD/x/x YYYY-MM-DD/x/x xx

xxx/xxx xxx xxx Discont. x YYYY-MM-DD/x/x YYYY-MM-DD/x/x xx

xxx/xxxxxxx xx/x/xx xxx/xxx xxx xxx None YYYY-MM-DD/x/x YYYY-MM-DD/x/x xx

xxx/xxxxxxx xx/x/xx xxx/xxx xxx xxx Interr. x YYYY-MM-DD/x/x YYYY-MM-DD/x/x xx

- # Reason for dose change/interruption: 1=As per protocol, 2=Adverse event, 3=Lack of efficacy, 5=Dosing error, 6=Dispensing error, 8=Technical problems, 9=Subject/guardian decision, 10=Physician decision, 12=Disease progression

Programming Note

1. Groups include Group 2A or Group 2B 2. Reason for dose permanent discontinuation is not captured on CRF DAR for INC280. 3. Use this listing for oral dosing. 4. Adjust content of listing according to study design and CRF to fit the needs of the study. Display all records for a subject together. Sorting for each subject by start date is recommended, however depending

on the study design, sorting by type of treatment prior to sorting by start day may result in a more useful display of data. 5. Footnotes displayed are for NCDS studies.

Country/ Subject identifier

Age/ Sex/ Race

Dose prescribed (mg) Frequency

daily dose (mg)

Dose modific. type

Reason #

Start date/ Cycle/ Study day

End date/ Cycle/ Study day

Total Duration (days)


Listing 16.2.5-3 Dose administration record for Nivolumab (Full analysis set) Group: xxxxx, <study drug: xxxxx>

Country/ Subject identifier

Age/ Sex/ Race

Dose prescribed (mg/kg)

Dose administered (mg)

Total volume admin. (mL)

Dose interrupted

Start date time/Cycle / Study day

End date time/Cycle / Study day

Duration (days)

Dose perm. disc .

Reason for perm. disc.*

xxx/xxxxxxx xx/x/xx xxx xxx xxx YYYY-MM-DD hh:mm/x/x

YYYY-MM-DD hh:mm/x/x

xx xx x

xxx xxx xxx Yes YYYY-MM-DD hh:mm/x/x


xx xx x

xxx xxx xxx YYYY-MM-DD hh:mm/x/x


xx xx

xxx xxx xxx YYYY-MM-DD hh:mm/x/x


xx xx

xxx/xxxxxxx xx/x/xx xxx xxx xxx YYYY-MM-DD

hh:mm/x/x YYYY-MM-DD hh:mm/x/x

xx xx

- * 2=Adverse event, 4=Lost to follow-up, 7=Pregnancy, 8=Progressive disease, 12=Study terminated by sponsor, 14=Subject/guardian decision, 15=Death, 998=Other.

Programming Note 1. Groups include Group 2A or Group 2B 2. Use this listing for non-oral dosing (e.g. IV). 3. Adjust content of listing according to study design and CRF to fit the needs of the study. Display all records for a subject together. Sorting for each subject by start date is recommended, however

depending on the study design, sorting by type of treatment prior to sorting by start day may result in a more useful display of data. 4. Footnotes displayed are for NCDS studies.


Listing 16.2.6-1 Overall response per patient by assessment cycle and group (Full analysis set) Group: xxxxx Country/ Age/ Tx Assessment Subject Sex/ start /Assessment date Cycle/ Response per identifier Race date /Study day* Cycle day investigator** Comment

* Study day is relative to the first day of treatment (day 1) **Response: CR=Complete response, PR=Partial response, SD=Stable disease, PD=Progressive disease, UNK=Unknown

USA/xxxx/xxxxx xx/F/Ca xxAAAxxxx 01/xxAAAxxxx/xxx xx/xx xx xxxxxx

02/xxAAAxxxx/xxx xx/xx xx xxxxxx


USA/xxxx/xxxxx xx/M/AA xxAAAxxxx 01/xxAAAxxxx/xxx xx/xx xx xxxxxx


Novartis Confidential WCLC2020 10-Mar-2021 (17:03) EGF816X2201C

Listing 16.2.6-2 Lesions evaluations (by RECIST criteria) (Full analysis set) Group: xxxxx Country/ Age/ Assessment Lesion Measurement Center/ Sex/ /Date number (Method* Dimension Subject Race /Cycle Lesion Type /location /specify) (mm) Lesion status

USA/xxxx/xxxxx xx/F/Ca Baseline

/xxAAAxxxx/xx Target 01 /Temporal xx /AAAAAAAA xx.xx

02 /Parietal xx /AAAAAAAA xx.xx 03 /Thalamus xx /AAAAAAAA xx.xx Non-target 01 /Lung xx /AAAAAAAA Absent

01/xxAAAxxxx/xx Target 01 /Temporal xx /AAAAAAAA xx.xx 02 /Parietal xx /AAAAAAAA xx.xx 03 /Thalamus xx /AAAAAAAA xx.xx Non-target 01 /Lung xx /AAAAAAAA Present

02/xxAAAxxxx/xx Target 01 /Temporal xx /AAAAAAAA xx.xx 02 /Parietal xx /AAAAAAAA xx.xx 03 /Thalamus xx /AAAAAAAA xx.xx Non-target 01 /Lung xx /AAAAAAAA Worsened

02 /Skin xx /AAAAAAAA Unknown

New 01 /Lung xx /AAAAAAAA

- Study day is relative to the first day of treatment(day 1)

Novartis Confidential WCLC2021 10-Mar-2021 (17:03) EGF816X2201C - * Method of measurement: 1=Physical exam, 2=Xray, 3=Xray chest, 4=CT scan (with contrast), 5=CT scan (without contrast),

6=Spiral CT (with contrast), 7=Spiral CT (without contrast), 8=MRI (with contrast), 9=MRI (without contrast), 10=Dynamic contrast enhanced MRI, 11=PET scan (18FDG PET), 12=PET scan (other agent), 13=Ultrasound, 14=Surgery, 15=Laboratory test, 16=Bone scan, 17=Endoscopy, 18=Bronchoscopy, 19=Colonoscopy, 20=Sigmoidoscopy, 21=External exam, 22=Internal, 23=Ishihara, 24=Skeletal Survey, 25=Photography, 998=Other specify.

Listing 16.2.6-4 Time to progression and death per patient by group (Full analysis set) Group: xxxxx Country/ Age/ Treatment Date of PD Date of Death Last date Center/ Sex/ start / end Progressed /study Last date free of Died (day*) / principle known alive Subject Race date (Y/N) day* progression /day* (Y/N) cause of death /day*

USA/xxxx/xxxxx xx/F/Ca xxAAAxxxx / xxAAAxxxx

xx xx / xx xx / xx xx xx / xx xx / xx

USA/xxxx/xxxxx xx/M/AA xxAAAxxxx / xxAAAxxxx xx xx / xx xx / xx xx xx / xx xx / xx

- * Study day is relative to the first day of treatment (day 1)

Novartis Confidential WCLC2021 10-Mar-2021 (17:03) EGF816X2201C

Programming Note: 1. Column Action taken’ is a combination of (1) all codes from the CRF field Action taken with study treatment' and (2) code 10 (concomitant medication or non-drug therapy) from the CRF field 'Medication

or therapies taken'. If no concomitant medication or non-drug therapy was taken, no code will be displayed. Choose 'Action taken' footnote according to the CRF version used. 2. For programs that do not use CTC grade, replace with Mild, Moderate, Severe. 3. Adapt the shell to display either all AEs, or subsets of AEs (e.g. SAEs, SAEs with fatal outcome, AEs leading to discontinuation…). 4. For DLTs Change title to “Dose limiting toxicities occurring during the <first> cycle<s>”. Change Safety set to Dose-determining set. 5. Flag those that occurred more than <100> days after last treatment, as defined in the SAP. 6. Display Ongoing’ under column End date/Study day’ if AE is ongoing at final exam / at time of data cut-off.

Listing 16.2.8-8 MET amplification, mutation and IHC expression status by cohort (Full analysis set) Group: xxxxx

Programming Note: 1. Flag patients having MET exon 14 skipping mutation, 2. Flag patients having MET H1094Y point mutation

a phase ii, multicenter, open-label study of egf816 in

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