PATIENTS AND METHODS · Web viewPK parameters were derived using standard non-compartmental methods...

TATTON: A multi-arm, phase Ib trial of osimertinib combined with selumetinib, savolitinib, or durvalumab in EGFR-mutant lung cancerOxnard GR, et al

SUPPLEMENTAL APPENDIXContentsPATIENTS AND METHODS....................................................................................................3

Patients....................................................................................................................................3

Exclusion criteria......................................................................................................................3

Key exclusion criteria in all arms...........................................................................................3

Additional exclusion criteria for the selumetinib arm...........................................................3

Additional exclusion criteria for the savolitinib arm.............................................................4

Additional exclusion criteria for durvalumab arm................................................................4

Eligibility criteria in all arms......................................................................................................5

Study design............................................................................................................................6

Dosing in the selumetinib arm..................................................................................................6

Combination dose finding.........................................................................................................6

RECIST v1.1 modification for durvalumab arm........................................................................6

Study assessments..................................................................................................................8

Safety.......................................................................................................................................8

Dose limiting toxicity.................................................................................................................8

Pharmacokinetics (PK).............................................................................................................9

Biomarker assessments.........................................................................................................12

Statistical analyses.................................................................................................................13

1

RESULTS...............................................................................................................................14

Tumor biomarker analysis......................................................................................................14

Supplementary Table S1. Summary of adverse events.........................................................15

Supplementary Table S2. Summary of all-causality serious adverse events........................17

Supplementary Table S3. Summary of adverse events leading to discontinuation of

osimertinib..............................................................................................................................20

Supplementary Table S4. Summary of adverse events leading to discontinuation of

selumetinib, savolitinib or durvalumab...................................................................................22

Supplementary Table S5. Pharmacokinetics.........................................................................25

Supplementary Table S6. Concordance between cobas tissue and NGS plasma tests.......28

Supplementary Table S7. Baseline plasma NGS analysis of 25 NGS T790M positive patients

who failed to respond to study treatment, ordered by PFS duration......................................29

Supplementary Figure S1. TATTON study design: patient enrollment..................................31

2

PATIENTS AND METHODS

Patients

Exclusion criteria

Key exclusion criteria in all arms

1. Treatment with an EGFR-TKI within approximately five half-lives of first dose of

study treatment.

2. Any cytotoxic chemotherapy, investigational agents, or other anti-cancer drugs

for treatment of advanced NSCLC within 14 days of first dose of study treatment.

3. Currently receiving (or unable to stop use prior to study treatment) medications or

herbal supplements known to be potent inducers of CYP3A4.

4. Osimertinib previously initiated in the TATTON study. Patients who received

osimertinib from other clinical studies were not excluded.

5. Radiotherapy within a limited field of radiation for palliation within 1 week of first

dose of study treatment.

6. Currently receiving warfarin sodium. Low-molecular-weight heparin was allowed.

7. Current leptomeningeal metastases or spinal cord compression. Brain

metastases were allowed if treated, asymptomatic and stable (not requiring

steroids within 4 weeks prior to first dose of study treatment).

8. Evidence of severe or uncontrolled systemic diseases.

9. Inadequate bone marrow reserve or organ function.

Additional exclusion criteria for the selumetinib arm

1. Prior or current treatment with selumetinib or any MEK, RAS, or RAF inhibitors.

3

2. Hypersensitivity to active or inactive excipients of osimertinib or selumetinib, or

drugs with a similar chemical structure to osimertinib or selumetinib.

Additional exclusion criteria for the savolitinib arm

1. Prior or current treatment with savolitinib or other MET inhibitors.

2. Current or prior use of medication known to be strong inhibitor of CYP1A2 and

CYP3A4 within 2 weeks of receiving first dose of savolitinib.

3. Hypersensitivity to active or inactive excipients of osimertinib or savolitinib, or

drugs with a similar chemical structure to osimertinib or savolitinib.

4. During the study patients should abstain from eating large amounts of grapefruit

and Seville oranges (<120 mL grapefruit juice or half a grapefruit or 1–2

teaspoons of Seville orange marmalade daily).

Additional exclusion criteria for durvalumab arm

1. Prior exposure to anti-PD-L1 or anti-PD1 antibodies.

2. Active or prior documented autoimmune or inflammatory disease within the past

3 years. Patients with vitiligo, alopecia, Grave’s disease, or psoriasis not requiring

systemic treatment in the past 3 years were not excluded.

3. History of organ transplant that requires the use of immunosuppressive

medications including, but not limited to, corticosteroids at doses greater than 10

mg/day of prednisone or equivalent, methotrexate, azathioprine, and tumor

necrosis factor alpha blockers. The use of immunosuppressive medications for

the management of investigational product-related adverse events (AEs) was

allowed. The use of inhaled and intranasal corticosteroids was allowed.

4. History of sarcoidosis syndrome.

4

5. Known history of tuberculosis.

6. Receipt of a live, attenuated vaccine within 30 days prior to first dose of

durvalumab.

7. Current or prior use of immunosuppressive medication within 28 days prior to first

dose of durvalumab, with the exception of inhaled or intranasal corticosteroids at

doses that do not exceed 10 mg/day of prednisone or equivalent.

8. Hypersensitivity to active or inactive excipients of osimertinib or durvalumab, or

drugs with a similar chemical structure to osimertinib or durvalumab.

Eligibility criteria in all arms

Patients were required to have adequate organ function and measurable disease

according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.

Patients could be enrolled following local/central assessment of EGFR T790M status

(positive or negative) from a biopsy taken following disease progression; tissue was

collected for confirmation of local test results and other molecular studies.

5

Study design

Dosing in the selumetinib arm

In the selumetinib arm, Asian patients received continuous selumetinib 25/50 mg PO

twice-daily (BD), while rest-of-world (ROW) patients received continuous selumetinib

50/75 mg BD, or intermittent selumetinib 75 mg BD days 1 and 4 of each week of

treatment, or 4 consecutive days on/3 days off.

Combination dose finding

Dose escalation and de-escalation was carried out as follows:

If no dose limiting toxicity (DLT) is observed in a cohort of three to six evaluable

patients, then dose escalation may occur. If one patient experiences a DLT in a

group of three or more evaluable patients, then the cohort will be expanded to six

evaluable patients. If only one DLT is observed in the cohort of six patients, then

dose escalation may occur. If two or more patients experience a DLT in a group of

up to six patients, irrespective of the number of patients enrolled, the dose will be

considered not tolerated and recruitment to the cohort and dose escalation will

cease. Dose de-escalation may be considered to define the combination dose

recommended for further clinical evaluation.

RECIST v1.1 modification for durvalumab arm

RECIST v1.1 was modified to take into consideration the unique response kinetics

that have been observed with immunotherapy in some subjects where responses to

immune therapies may occur after progressive disease (PD) is reported.44 Patients in

the durvalumab arm were treated and followed up post-initial progression until

subsequent disease progression (confirmed progression).

6

In this study, a scan confirming progression was required at no less than 4

weeks after initial assessment of PD, and preferably at the next scheduled visit.

Confirmed disease progression was defined as: ≥20% increase in sum diameters of

target lesions compared with the nadir at two consecutive visits; and/or significant

progression of non-target lesions (NTLs) or new lesions (NLs) at the confirmatory PD

time point compared with the first time point where progression of NTLs or NLs were

identified; and/or additional new unequivocal lesions at the confirmatory PD time

point, compared with the first time point NLs were identified.

If progression was not confirmed, the overall visit response would be

assessed as stable disease/partial response or complete response and the subject

should continue scheduled RECIST 1.1. computed tomography/magnetic resonance

imaging scans. If progression was confirmed, the overall visit response would be

assessed as PD.

7

Study assessments

Safety

AEs were collected from informed consent until end of follow-up (28 days after study

treatment discontinuation in the selumetinib and savolitinib arms, 3 months in the

durvalumab arm), graded according to the National Cancer Institute Common

Terminology Criteria for Adverse Events v4.03.

Dose limiting toxicity

DLT was defined as an AE or abnormal laboratory value considered unrelated to

disease progression, intercurrent illness, or concomitant medications that occurred

from the first dose of study treatment up to the last day of Cycle 1, and met any of

the following criteria despite optimal therapeutic intervention: a hematological toxicity

of grade ≥4 present for more than 4 days; grade 3 thrombocytopenia with bleeding;

febrile neutropenia; a non-hematological toxicity of grade ≥3; any other clinically

significant toxicity judged as a DLT by the safety review committee, or resulting in a

disruption of dosing schedule for >7 days. Additional DLTs that applied to the

durvalumab combination arm only were defined as: any grade 4 immune-related AE

(irAE); any grade ≥3 colitis; any grade 3 or 4 non-infectious pneumonitis, any grade 3

irAE, excluding colitis or pneumonitis, that did not downgrade to grade ≤2 within 3

days after onset despite maximal supportive care including systemic corticosteroids,

or downgrade to grade ≤1 within 14 days after onset; any grade ≥2 pneumonitis or

interstitial lung disease that did not resolve to grade 1 within 3 days of initiation of

maximal supportive care.

8

Pharmacokinetics (PK)

The PK analysis set included patients with reportable study drug plasma

concentrations and no important AEs or protocol deviations potentially impacting PK.

Serial blood samples were collected for evaluation of PK parameters pre-

dose, at Cycle 1 day 8 and 15, Cycles 2–6 day 1, and then every 8 weeks until

disease progression and at multiple time points post-dose on day 1 of Cycles 1 and

2. Study drug plasma concentrations were determined using a validated liquid

chromatography-tandem mass spectrometry (LC-MS/MS) assay (Covance labs,

Harrogate, UK) with a lower limit of detection of 0.825 ng/mL, 2 ng/mL and 1 ng/mL

for osimertinib, selumetinib, savolitinib, and their metabolites, respectively.

Durvalumab PK samples were collected pre-dose and at the end of infusion at Cycle

1 day 1 and 15, and Cycles 2–7 day 1, and were analyzed using an ELISA assay.

PK parameters were derived using standard non-compartmental methods using

Phoenix WinNonlin v6.4 (Certara, Princeton, New Jersey, US).

Following osimertinib 80 mg orally (PO) once-daily (OD) plus selumetinib,

Savolitinib, or durvalumab at steady state, a flat PK profile with limited difference

between Css max and Css min for osimertinib and its desmethyl metabolites

(AZ5104 and AZ7550) was observed. Geometric mean AUCss and Css max for

osimertinib was 10040–15990 nM/h and 521.2–960.5 nM, respectively. Inter-patient

variability for AUCss and Css max was approximately 17–65% and 17–75%,

respectively. Exposure to osimertinib was similar regardless of the co-administered

drug and its dose levels or regimen, or by ethnicity. There was minimal to no effect of

the combination drugs on the PK of osimertinib. Similarly, osimertinib had minimal to

no effect on the PK of selumetinib, savolitinib, or durvalumab.

9

Following administration of selumetinib 25–75 mg twice-daily (BD)

continuously or intermittently in Asian or non-Asian patients, selumetinib was rapidly

absorbed and then rapidly eliminated, with arithmetic mean t1/2λz values ranging from

approximately 2.1–5.0 hours. Based on arithmetic mean Rac values of 0.9–1.4, no-

to-minimal accumulation of selumetinib in plasma was observed after BD dosing.

Selumetinib PK appeared to be time-independent; dose-dependent increases in

selumetinib geometric mean Cmax and AUCs were observed on Cycle 1 day 1 and

Cycle 2 day 1. Systemic exposure, as assessed by geometric mean AUC(0–12), to the

metabolite, N-desmethyl selumetinib, was approximately 5–8% of that to selumetinib.

PK parameters for selumetinib and N-desmethyl selumetinib were generally similar

between Asian and non-Asian patients following continuous 50 mg dosing, and

among the continuous and intermittent dosing regimens at 75 mg BD in non-Asians.

Following administration of savolitinib 600 or 800 mg once daily, savolitinib

was rapidly absorbed and rapidly eliminated, with median tmax values of

approximately 1–2 hours and arithmetic mean t1/2λz values of approximately 3.0–3.5

hours. Accumulation of savolitinib and its metabolites (AZD6094M2 and

AZD6094M3) in plasma was not observed (arithmetic mean Rac of approximately

0.6–0.9) on Cycle 2 day 1 at 600 mg dose, as expected based on the short t1/2λz with

once-daily dosing. The range of individual Cmax and AUC values was similar between

the 600 mg and 800 mg doses for parent and metabolites on Cycle 1 day 1, given

the small sample size and high between-patient variability. Systemic exposure to

AZD6094M2 and AZD6094M3 was approximately 21–38% and 10–13%,

respectively, of that to savolitinib on day 1 of Cycles 1 and 2.

Following a 1-hour IV infusion of durvalumab on Cycle 1 day 1, durvalumab

Cmax was achieved at or near the end of infusion, and near dose-proportional

10

increases in geometric mean Cmax and AUC(0–336) were observed as durvalumab

dosage increased from 3–10 mg/kg.

11

Biomarker assessments

Patients were identified as T790M positive if either tumor or cell-free DNA analysis

detected T790M, while patients were identified as T790M negative if available

genotyping (tumor, plasma, or both) did not detect T790M.

MET amplification by FISH was defined as ≥5 copies of MET averaged over

50 cells scored. PD-L1 expression by immunohistochemistry was defined as ≥25%

tumor cell membrane expression.

12

Statistical analyses

Sample size was based on the desire to obtain adequate safety, tolerability, and PK

data to define the recommended dose for further clinical evaluation, while exposing

as few patients as possible to study medications and procedures. The total number

of patients was dependent on the number of combination-dose-level evaluations

necessary to define the recommended dose for further clinical evaluation. Patients

were enrolled to ensure a minimum of three and a maximum of six evaluable

patients per dose cohort.

13

RESULTS

Tumor biomarker analysis

Of 77 patients in the safety analysis set, tumor tissue EGFR genotyping (cobas) was

available for 56, ctDNA NGS was available for 73, and both were available for 53. Of

48 T790M-positive cases, 23 were detected in tumor and plasma, while six were

detected in tumor only (two without a valid plasma result), and 19 in plasma only (13

without a valid tissue result) (Table S6). Positive percent agreement (PPA) between

cobas® EGFR Mutation Test v2 (Roche Molecular Systems, Inc) tumor data and

plasma NGS for detecting known EGFR driver mutations was 97% (30/31) for Exon

19 deletion, 79% (23/29) for T790M, and 100% (13/13) for L858R. Negative percent

agreement (NPA) between cobas tumor data and plasma genotyping was 91%

(20/22) and 90% (36/40) for Exon 19 deletion and L858R, respectively, and 83%

(20/24) for T790M.

Of 73 patients with ctDNA NGS data, EGFRm (ex19del or L858R) was not

detectable in 10, indicating insufficient tumor content for genomic profiling. Of the 63

patients with detectable EGFRm, 42 were T790M positive, of which 25 were

evaluable and failed to respond to treatment. NGS detected a range of co-occurring

resistance mutations in these patients (Table S7) including six PIK3CA mutations,

two HER2 mutations with concurrent HER2 amplifications, three MET amplifications,

one KRAS mutation, and one RET-fusion.

14

Supplementary Table S1. Summary of adverse events

Patients with an event n, (%)

Selumetinib (continuous, Asia)

Selumetinib (continuous, ROW)

Selumetinib 75 mg BD (intermittent,

ROW)

Savolitinib Durvalumab

25 mg BD

(n=7)

50 mg BD

(n=6)

50 mg BD

(n=6)

75 mg BD

(n=6)

Days 1 and 4 each week(n=3)

4 days on/3

days off(n=8)

600 mg QD

(n=12)

800 mg QD

(n=6)

3 mg/kg Q2W

(n=10)

10 mg/kg Q2W

(n=13)

Any AE Causally related to osimertiniba

Causally related to sel, sav or durva

Causally related to combinationa

6 (85.7)2 (28.6)4 (57.1)3 (42.9)

6 (100.0)3 (50.0)5 (83.3)5 (83.3)

6 (100.0)1 (16.7)5 (83.3)6 (100.0)

6 (100.0)5 (83.3)5 (83.3)5 (83.3)

3 (100.0)0

2 (66.7)3 (100.0)

8 (100.0)6 (75.0)3 (37.5)7 (87.5)

12 (100.0)5 (41.7)9 (75.0)6 (50.0)

6 (100.0)2 (33.3)6 (100.0)5 (83.3)

10 (100.0)8 (80.0)4 (40.0)9 (90.0)

13 (100.0)8 (61.5)4 (30.8)6 (46.2)

Any grade ≥3 AE Causally related to osimertiniba

Causally related to sel, sav or durva

Causally related to combination

2 (28.6)1 (14.3)1 (14.3)1 (14.3)

5 (83.3)1 (16.7)3 (50.0)1 (16.7)

2 (33.3)0

1 (16.7)1 (16.7)

6 (100.0)1 (16.7)2 (33.3)4 (66.7)

1 (33.3)000

5 (62.5)00

4 (50.0)

9 (75.0)1 (8.3)

3 (25.0)2 (16.7)

5 (83.3)0

2 (33.3)1 (16.7)

6 (60.0)1 (10.0)1 (10.0)2 (20.0)

5 (38.5)1 (7.7)

02 (15.4)

Any AE leading to death Causally related to any treatmenta

00

00

00

1 (16.7)1 (16.7)

00

00

1 (8.3)0

2 (33.3)0

1 (10.0)0

00

Any AE leading to discontinuation of: osimertinib sel, sav, or durv

1 (14.3)3 (42.9)

1 (16.7)2 (33.3)

01 (16.7)

3 (50.0)5 (83.3)

00

1 (12.5)2 (25.0)

1 (8.3)3 (25.0)

2 (33.3)2 (33.3)

3 (30.0)4 (40.0)

3 (23.1)5 (38.5)

15

Any AE leading to dose interruption or reduction of: osimertinib sel, sav, or durv

4 (57.1)2 (28.6)

4 (66.7)6 (100.0)

1 (16.7)6 (100.0)

3 (50.0)3 (50.0)

1 (33.3)2 (66.7)

5 (62.5)6 (75.0)

6 (50.0)5 (41.7)

1 (16.7)5 (83.3)

4 (40.0)1 (10.0)

4 (30.8)3 (23.1)

Any SAE Causally related to any treatment Causally related to sel, sav, or durva

Causally related to combinationa

1 (14.3)1 (14.3)1 (14.3)

0

2 (33.3)1 (16.7)1 (16.7)

0

0000

3 (50.0)3 (50.0)2 (33.3)1 (16.7)

1 (33.3)000

4 (50.0)1 (12.5)

01 (12.5)

8 (66.7)1 (8.3)1 (8.3)

0

3 (50.0)1 (16.7)1 (16.7)1 (16.7)

7 (70.0)4 (40.0)2 (20.0)2 (20.0)

3 (23.1)1 (7.7)

01 (7.7)

Any SAE leading to discontinuation of: osimertinib sel, sav or durv

01 (14.3)

00

00

2 (33.3)3 (50.0)

00

01 (12.5)

02 (16.7)

2 (33.3)2 (33.3)

2 (20.0)2 (20.0)

1 (7.7)1 (7.7)

Any SAE leading to dose interruption or reduction of: osimertinib sel, sav or durv

1 (14.3)0

1 (16.7)1 (16.7)

00

2 (33.3)1 (16.7)

1 (33.3)1 (33.3)

2 (25.0)1 (12.5)

3 (25.0)3 (25.0)

1 (16.7)1 (16.7)

3 (30.0)1 (10.0)

1 (7.7)1 (7.7)

Patients with multiple events in the same category were counted once in that category. Patients with events in more than one category were counted once in each of those categories. Includes adverse events with an onset date on or after the date of first dose and up to and including 38 days following the date of last dose of study medication.a Possibly related, as assessed by the Investigator.

AE, adverse event; BD, twice-daily; d, day; durv, durvalumab; Q2W, once every 2 weeks; OD, once-daily; ROW, rest of world; SAE, serious AE; sav, savolitinib; sel, Selumetinib

16

Supplementary Table S2. Summary of all-causality serious adverse events

Patients with an SAE, (%)



Selumetinib 75 mg BD (intermittent, ROW)


25 mg BD

(n=7)

50 mg BD(n=6)

50 mg BD(n=6)

75 mg BD(n=6)

Days 1 and 4

each week(n=3)

4 days on/3 days

off(n=8)

600 mg QD

(n=12)

800 mg QD

(n=6)

3 mg/kg Q2W

(n=10)

10 mg/kg Q2W

(n=13)

Patients with any SAE 1 (14.3) 2 (33.3) 0 3 (50.0) 1 (33.3) 4 (50.0) 8 (66.7) 3 (50.0) 7 (70.0) 3 (23.1)

Bacteremia 1 (14.3) 0 0 0 0 0 0 0 0 0Viral gastroenteritis 0 1 (16.7) 0 0 0 0 0 0 0 0

Dizziness 0 1 (16.7) 0 0 0 0 0 0 0 0Colitis 1 (14.3) 0 0 0 0 0 0 0 0 0Diarrhea 0 1 (16.7) 0 2 (33.3) 0 0 0 0 0 0Uterine prolapse 1 (14.3) 0 0 0 0 0 0 0 0 0Asthenia 0 1 (16.7) 0 0 0 0 0 0 0 0Dehydration 0 0 0 1 (16.7) 0 0 0 0 0 0Nausea 0 0 0 2 (33.3) 0 0 0 0 0 0Vomiting 0 0 0 1 (16.7) 0 0 0 0 0 0Hyperbilirubinemia 0 0 0 1 (16.7) 0 0 0 0 0 0Death 0 0 0 1 (16.7) 0 0 0 0 0 0Blood creatinine increased 0 0 0 1 (16.7) 0 0 0 0 0 0

Infectious enterocolitis 0 0 0 0 1 (33.3) 0 0 0 0 0

Lung infection 0 0 0 0 0 1 (12.5) 0 0 0 0Pneumonia 0 0 0 0 0 1 (12.5) 0 0 1 (10.0) 0Dyspnea 0 0 0 0 0 1 (12.5) 1 (8.3) 0 0 1 (7.7)Hemoptysis 0 0 0 0 0 1 (12.5) 0 0 0 0

17






25 mg BD

(n=7)

50 mg BD(n=6)

50 mg BD(n=6)

75 mg BD(n=6)

Days 1 and 4

each week(n=3)

4 days on/3 days

off(n=8)

600 mg QD

(n=12)

800 mg QD

(n=6)

3 mg/kg Q2W

(n=10)

10 mg/kg Q2W

(n=13)

Abdominal distension 0 0 0 0 1 (33.3) 0 0 0 0 0

Back pain 0 0 0 0 0 1 (12.5) 0 0 0 0Fatigue 0 0 0 0 0 1 (12.5) 0 0 0 0Viral pneumonia 0 0 0 0 0 0 1 (8.3) 0 0 0Upper respiratory tract infection 0 0 0 0 0 0 1 (8.3 0 0 0

Malignant pleural effusion 0 0 0 0 0 0 1 (8.3) 0 0 0

Febrile neutropenia 0 0 0 0 0 0 1 (8.3) 0 0 0

Cerebrovascular accident 0 0 0 0 0 0 0 1 (16.7) 0 0

Thrombotic stroke 0 0 0 0 0 0 0 1 (16.7) 0 0Organizing pneumonia 0 0 0 0 0 0 1 (8.3) 0 0 0

Pleural effusion 0 0 0 0 0 0 1 (8.3) 0 0 0Pulmonary embolism 0 0 0 0 0 0 1 (8.3) 0 0 0

Abdominal pain 0 0 0 0 0 0 1 (8.3) 0 0 0Oral inflammationa 0 0 0 0 0 0 1 (8.3) 0 0 0Myalgia 0 0 0 0 0 0 1 (8.3) 0 0 0Chills 0 0 0 0 0 0 1 (8.3) 0 0 0Pyrexia 0 0 0 0 0 0 2 (16.7) 0 1 (10.0) 0Neutrophil count 0 0 0 0 0 0 0 1 (16.7) 0 0

18






25 mg BD

(n=7)

50 mg BD(n=6)

50 mg BD(n=6)

75 mg BD(n=6)

Days 1 and 4

each week(n=3)

4 days on/3 days

off(n=8)

600 mg QD

(n=12)

800 mg QD

(n=6)

3 mg/kg Q2W

(n=10)

10 mg/kg Q2W

(n=13)

decreasedAbdominal infection 0 0 0 0 0 0 0 0 0 1 (7.7)

Cellulitis 0 0 0 0 0 0 0 0 1 (10.0) 0Hyponatremia 0 0 0 0 0 0 0 0 1 (10.0) 0Superior vena cava syndrome 0 0 0 0 0 0 0 0 1 (10.0) 0

Bronchial obstruction 0 0 0 0 0 0 0 0 1 (10.0) 0

Hypoxia 0 0 0 0 0 0 0 0 1 (10.0) 0ILDa 0 0 0 0 0 0 0 0 2 (20.0) 1 (7.7)Rasha 0 0 0 0 0 0 0 0 1 (10.0) 0Renal impairment 0 0 0 0 0 0 0 0 0 1 (7.7)Other 0 0 0 0 0 0 0 1 (16.7) 0 0

Patients with multiple SAEs are counted once for each event.Includes adverse events with an onset date on or after the date of first dose and up to and including 28 days following the date of last dose of study medication.aRepresents grouped term reporting.

AE, adverse event; BD, twice-daily; ILD, interstitial lung disease; Q2W, once every 2 weeks; OD, once-daily; ROW, rest of world; SAE, serious adverse event

19

Supplementary Table S3. Summary of adverse events leading to discontinuation of osimertinib

Patients with an AE leading to discontinuation of osimertinib, (%)





25 mg BD(n=7)

50 mg BD(n=6)

50 mg BD(n=6)

75 mg BD(n=6)

Days 1 and 4

each week(n=3)

4 days on/3 days

off(n=8)

600 mg QD

(n=12)

800 mg QD

(n=6)

3 mg/kg Q2W

(n=10)

10 mg/kg Q2W

(n=13)

Patients with any AE leading to discontinuation of osimertinib

1 (14.3) 1 (16.7) 0 3 (50.0) 0 1 (12.5) 1 (8.3) 2 (33.3) 3 (30.0) 3 (32.1)

Renal impairment 1 (14.3) 0 0 0 0 0 0 0 0 0Blood creatinine increased 0 1 (16.7) 0 0 0 0 0 0 0 0

Pneumonitis 0 0 0 1 (16.7) 0 0 0 0 0 0Diarrhea 0 0 0 1 (16.7) 0 0 0 0 0 0Death 0 0 0 1 (16.7) 0 0 0 0 0 0Decreased appetite 0 0 0 0 0 1 (12.5) 0 0 0 0

Dry mouth 0 0 0 0 0 1 (12.5) 0 0 0 0Fatigue 0 0 0 0 0 1 (12.5) 0 0 0 0Alanine aminotransferase increased

0 0 0 0 0 0 1 (8.3) 0 0 0

Aspartate aminotransferase increased

0 0 0 0 0 0 1 (8.3) 0 0 0

20

Thrombotic stroke 0 0 0 0 0 0 0 1 (16.7) 0 0


Hyponatremia 0 0 0 0 0 0 0 0 1 (10.0) 0Pneumonitis 0 0 0 0 0 0 0 0 1 (10.0) 2 (15.4)Pneumonia 0 0 0 0 0 0 0 0 1 (10.0) 1 (7.7)

Patients with multiple AEs are counted once for each event.AE, adverse event; BD, twice-daily; Q2W, once every 2 weeks; OD, once-daily; ROW, rest of world

21

Supplementary Table S4. Summary of adverse events leading to discontinuation of selumetinib, savolitinib or durvalumab

Patients with an AE leading to discontinuation of selu,savo, or durv, (%)





25 mg BD(n=7)

50 mg BD(n=6)

50 mg BD(n=6)

75 mg BD(n=6)

Days 1 and 4

each week(n=3)

4 days on/3 days

off(n=8)

600 mg QD

(n=12)

800 mg QD

(n=6)

3 mg/kg Q2W

(n=10)

10 mg/kg Q2W

(n=13)

Patients with any AE leading to discontinuation of selu,savo, or durv

3 (42.9) 2 (33.3) 1 (16.7) 5 (83.3) 0 3 (37.5) 3 (25.0) 2 (33.3) 4 (40.0) 5 (38.5)

Renal impairment 1 (14.3) 0 0 0 0 0 0 0 0 0Pyrexia 2 (28.6) 0 0 0 0 0 0 0 0 0Colitis 1 (14.3) 0 0 0 0 0 0 0 0 0Diarrhea 1 (14.3) 0 0 3 (50.0) 0 0 0 0 0 0Rash maculo-papular 1 (14.3) 0 0 0 0 0 0 0 0 0

Stomatitis 1 (14.3) 0 0 0 0 0 0 0 0 0Blood creatinine increased 0 1 (16.7) 0 0 0 0 0 0 0 0

Left ventricular dysfunction 0 1 (16.7) 0 0 0 0 0 0 0 0

Ejection fraction decreased 0 0 1 (16.7) 00 0 1 (12.5) 0 0 0 0

Rash macular 0 0 0 1 (16.7) 0 0 0 0 0 0Pneumonitis 0 0 0 1 (16.7) 0 0 0 0 1 (10.0) 3 (23.0)Death 0 0 0 1 (16.7) 0 0 0 0 0 0Nausea 0 0 0 1 (16.7) 0 0 0 1 (16.7) 0 0

22

Patients with an AE leading to discontinuation of selu,savo, or durv, (%)





25 mg BD(n=7)

50 mg BD(n=6)

50 mg BD(n=6)

75 mg BD(n=6)

Days 1 and 4

each week(n=3)

4 days on/3 days

off(n=8)

600 mg QD

(n=12)

800 mg QD

(n=6)

3 mg/kg Q2W

(n=10)

10 mg/kg Q2W

(n=13)

Vomiting 0 0 0 1 (16.7) 0 0 0 0 0 0Dry mouth 0 0 0 0 0 1 (12.5) 0 0 0 0Fatigue 0 0 0 0 0 2 (25.0) 0 0 0 0Back pain 0 0 0 0 0 1 (12.5) 0 0 0 0Dyspnea 0 0 0 0 0 0 1 (8.3) 0 0 0Alanine aminotransferase increased

0 0 0 0 0 0 1 (8.3) 0 0 0

Aspartate aminotransferase increased

0 0 0 0 0 0 1 (8.3) 0 0 0

Myalgia 0 0 0 0 0 0 1 (8.3) 0 0 0Thrombotic stroke 0 0 0 0 0 0 0 1 (16.7) 0 0


Hyponatremia 0 0 0 0 0 0 0 0 1 (10.0) 0White blood cell count decreased 0 0 0 0 0 0 0 0 1 (10.0) 1 (7.7)

Pyrexia 0 0 0 0 0 0 0 0 1 (10.0) 0Neutrophil count decreased 0 0 0 0 0 0 0 0 0 1 (7.7)

Pneumonia 0 0 0 0 0 0 0 0 0 1 (7.7)

Patients with multiple AEs are counted once for each event.

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Abbreviations: AE, adverse event; BD, twice-daily; Q2W, once every 2 weeks; QD, once-daily; ROW, rest of world

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Supplementary Table S5. Pharmacokinetics

Single dose (Cycle 1 day 1) Multiple dose (Cycle 2 day 1)

Compound

Cmax, geometric mean, nM (%CV)

Tmax, median, h

(range)

AUC0-24, geometric mean, nM.h, (%CV)

T1/2, arithmetic mean, h (SD)

Cssmax, geometric mean, nM (%CV)

Tssmax, median, h

(range)

Cssmin, geometric mean, nM (%CV)

AUCτ, geometric mean, nM.h (%CV)

Rac,

Osimertinib + durvalumab 3 mg/kg

230 (54.5)

4.08 (4.0, 7.0)

3771 (53.3) NC

521.2 (42.4)

6.9 (2.0, 23.4)

276.0 (64.0)

11480 (29.9) 2.8 (1.4)

+ durvalumab 10 mg/kg

199.1 (57.7)

6.0 (2.1, 8.0)

3372 (68.0) NC

526.2 (42.0)

6.0 (3.0, 23.3)

271.5 (84.0)

10170 (48.9) 3.4 (1.4)

+ savolitinib 600 mg

328.8 (61.8)

4.0 (3.0, 6.0)

5483 (54.7) NC

783.3 (59.7)

4.0 (3.9, 8.0)

401.3 (94.9)

14470 (60.0) 2.7 (1.5)

+ savolitinib 800 mg

327.0 (69.1)

5.9 (4.0, 6.0)

5047 (73.4) NC

960.5 (17.1)

6.0 (4.0, 8.0)

518.1 (13.5)

15990 (16.3) 2.7 (1.6)

+ selumetinib 25 mg (continuous, Asian)

200.9 (53.5)

4.0(4.0, 23.8)

3438 (53.7) NC

807.2 (29.6)

7.0 (4.0, 24.0)

438.2 (55.9)

14860 (38.8) 4.6 (1.8)


153.9 (64.0)

5.0 (2.0, 8.1)

2422 (67.0) NC

654.8 (16.9)

7.0 (4.0, 8.0)

401.2 (28.8)

12480 (21.4) 6.0 (3.2)

+ selumetinib 50 mg (continuous, ROW)

204.2 (89.6)

5.1 (2.0, 6.2)

3552 (63.4) NC

573.7 (43.5)

5.9 (4.0, 7.8)

341.0 (36.9)

10040 (43.2) 3.4 (NA)

25


256.3 (28.7)

4.2 (3.8, 6.1)

3910 (33.3) NC 346, 576 6.0, 6.0 191, 348

6530, 11200 2.2, 4.7

+ selumetinib 75 mg (int days 1 and 4 each week, ROW)

130.1 (71.2)

8.0 (6.1, 23.8)

1360 (NA) NC

595.8 (75.3)

7.9 (3.9, 7.9)

424.7 (54.5)

11790 (64.9) 4.4 (NA)

+ selumetinib 75 mg (int 4 days on/3 days off, ROW)

240.5 (47.1)

4.0 (3.9, 7.8)

3547 (40.5) NC

636.0 (52.1)

4.6 (4.0, 6.0)

329.5 (35.3)

10270 (53.3) 2.0, 6.1

Savolitinib600 mg + osimertinib

4262 (43.2)

2.0 (0.9, 4.0)

28180 (10.9) 3.5 (0.7)

2522 (43.3)

1.0(0.95, 2.0)

30.0 (143)

14950 (26.6)

0.61 (0.15)

800 mg + osimertinib

3812 (74.0)

1.0 (1.0, 5.3)

18180 (115.2) 3.0 (0.2)

2430 (NA) 4.0 (NA)

24.0 (NA) NC NC

Selumetinib


379.5 (92.5)

1.5 (0.95, 4.1)

1450 (32.4)

2.2 (0.35)

485.3 (8.0)

2.0 (1.0, 2.0)

26.2 (28.6)

1340, 1440 0.7, 0.86


1033 (67.3)

1.5 (0.9, 2.0)

2834 (56.5)

2.32 (0.37)

716.9 (58.6)

2.0 (1.9, 4.0)

126.4 (31.7)

3260, 3660 0.86, 2.6


1143 (54.9)

1.0 (0.9, 2.0)

2792 (31.7)

2.42 (0.65)

1051 (41.4)

1.9 (0.9, 2.6)

134.6 (59.9)

3743 (40.0)

1.38(0.5)

+ selumetinib 75 mg

1308 (80.7)

1.5 (1.0, 2.1)

3933 (74.2)

2.59 (0.56)

1750 (NA)

1.0 (NA) 199 (NA)

5970(NA)

1.05(NA)

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(continuous, ROW)

+ selumetinib 75 mg (int days 1 and 4 each week, ROW)

1627 (137.4)

1.0 (1.0, 1.1)

4840 (60.6)

2.47 (0.58) NC NC NC

4190 (39.7)

0.88(0.18)

+ selumetinib 75 mg (int 4 days on/3 days off, ROW)

1249 (62.6)

2.0 (0.9, 2.1)

3778 (54.6)

2.11 (0.77) NC NC NC

3422(124.4) 0.3, 1.4

Int, intermittent; NC, not calculable; ROW, rest of world

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Supplementary Table S6. Concordance between cobas tissue and NGS plasma tests

Plasma next-generation sequencing test results

Cobas tissue test results, n

T790M positive (n=42)

T790M negative(n=31)

Not tested (n=4)

Ex19del positive(n=44)

Ex19del negative(n=29)

Not tested(n=4)

L858R positive(n=17)

L858R negative(n=56)

Not tested(n=4)

Tissue positive 23 4 2 30 2 1 13 4 2Tissue negative 6 20 1 1 20 2 0 36 1

Not tested/missing 13 7 1 13 7 1 4 16 1Percent agreement,

% (95% CI)a

Positive percent agreement (sensitivity)

23/29: 79% (60–92%)

30/31: 97%(83–100%)

13/13: 100% (75–100%)

Negative percent agreement (specificity)

20/24: 83% (63–95%)

20/22: 91% (71–99%)

36/40: 90% (76–97%)

Overall concordance 43/53: 81% (68–91%)

50/53: 94% (84–99%)

49/53: 92% (82–98%)

aCobas tissue result used as the reference.

CI, confidence interval; Ex19del, exon 19 deletion; NGS, next-generation sequencing

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Supplementary Table S7. Baseline plasma NGS analysis of 25 NGS T790M positive patients who failed to respond to study

treatment, ordered by PFS duration

Patient Combination treatment

Prior T790M-directed therapy

Best objective response

PFS (days)

Tissue T790M status

NGS T790M AF (%)

NGSEGFRm

NGSEGFRm AF (%)

NGS co-occurring mutations of note

1 Continuous selumetinib

No PD 27 Positive 0.35 Ex19del 0.68

2 Intermittent selumetinib

Osimertinib SD 31 Not detected

0.23 L858R 5.35

3 Savolitinib Osimertinib PD 37 Positive 14.69 Ex19del 28.724 Savolitinib No PD 38 Positive 11.23 Ex19del 45.63 PIK3CA E542K (0.8%)5 Intermittent

selumetinibNo PD 41 No test 0.19 Ex19del 9.70

6 Durvalumab No SD 41 Positive 3.01 Ex19del 10.647 Savolitinib No PD 42 Positive 0.07 L858R 3.40 PIK3CA E545K (8.2%)8 Continuous

selumetinibNo PD 42 No test 0.87 L858R 67.45 HER2 G131R (5.9%)

HER2 amp (2.9 copies)

9 Durvalumab No PD 42 Not detected

1.75 L858R 16.65 HER2 S310F (28%) HER2 amp (3.2

copies)PIK3CA M1043I

(1.0%)MET amp (2.3 copies)

10 Durvalumab No PD 42 No test 6.26 Ex19del 42.4311 Durvalumab No SD 42 Not

detected4.79 Ex19del 9.87

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Osimertinib SD 48 No test 1.84 Ex19del 33.74 PIK3CA E545K (4.6%)KRAS G12V (1.6%)RET-CCDC6 fusion

HER2 amp (3.6 copies)

MET amp (2.3 copies)13 Savolitinib No SD 49 Positive 1.18 L858R 0.6514 Intermittent

selumetinibNo PD 59 Not

detected14.13 Ex19del 40.14

15 Savolitinib No PD 74 Not detected

0.81 Ex19del 10.25

16 Savolitinib No SD 82 Positive 2.87 L858R 63.3917 Durvalumab No SD 84 No test 1.19 Ex19del 15.45 PIK3CA H1047R

(0.11%)18 Continuous

selumetinibNo SD 126 Positive 25.21 Ex19del 81.17


No SD 126 Not detected

0.72 Ex19del 9.60


Rociletinib SD 131 Positive 21.58 Ex19del 53.58

21 Durvalumab Osimertinib SD 163 Positive 22.45 L858R 20.9722 Intermittent

selumetinibNo SD 167 No test 4.63 Ex19del 13.70


No SD 203 No test 0.05 L858R 52.93 PIK3CA R38C (10.7%)Met amp (2.3 copies)


No SD 217 Positive 10.31 Ex19del 66.13

25 Savolitinib No SD 454 Positive 2.89 Ex19del 12.23

AF, allelic fraction; EGFRm, EGFR sensitizing mutation; Ex19de, exon 19 deletion; PD, progressive disease; PFS, progression-free survival, SD, stable disease

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Supplementary Figure S1. TATTON study design: patient enrollment

Markers indicate time of patient enrollment; boxes indicate enrollment cohorts

ROW, rest of world

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