Adjuvant EGFR-Targeted Therapy as a Game Changer: How to Implement New Standards of Care in Multimodal Management of Stage I-III EGFR-Mutated NSCLC

Therapies for EGFR-Mutated NSCLC
Current Approvals and Indications1
Full abbreviations, accreditation, and disclosure information available at PeerView.com/MHD40
1. https://www.fda.gov/drugs/resources-information-approved-drugs/hematologyoncology-cancer-approvals-safety-notifications.
Third-Generation
Irreversible EGFR TKI
Osimertinib
Metastatic
Early Stage
Third-Generation
Irreversible EGFR TKI
Osimertinib
• 1L for EGFR exon 19 deletions or L858R
mutations
• Treatment of T790M-positive NSCLC with
progression on or after EGFR TKI therapy
EGFR/MET Bispecific
Antibody
Amivantamab
• 2L for EGFR exon 20 insertion mutations
in patients whose disease has progressed
on or after platinum-based chemotherapy
Irreversible EGFR/HER2
(Exon 20 Insertion) TKI
Mobocertinib
• 2L for EGFR exon 20 insertion mutations
in patients whose disease has progressed
on or after platinum-based chemotherapy
EGFR TKI + VEGFR2
Antagonist
Erlotinib + Ramucirumab
• 1L for EGFR exon 19 deletions or L858R
mutations
• Adjuvant therapy after tumor resection in patients with stage IB-IIIA NSCLC
whose tumors have EGFR exon 19 deletions or exon 21 L858R mutations
First-Generation
Reversible EGFR TKIs
Gefitinib Erlotinib
• 1L for EGFR exon 19
deletions or L858R
mutations
deletions or L858R
mutations
Second-Generation
Irreversible EGFR TKIs
Afatinib Dacomitinib
deletions or L858R,
S768I, L861Q, and/or
G719X mutations
deletions or L858R
mutations

Addressing Unmet Needs and Improving Outcomes in Early-Stage NSCLC
New Role for Adjuvant EGFR-Targeted Therapy
• About 30% of patients with NSCLC present with resectable
disease at diagnosis1-3
• Surgery with curative intent is the primary treatment for these
patients4
• Adjuvant cisplatin-based chemotherapy is recommended for
patients with resectable stage II-IIIA NSCLC and select patients
with stage IB disease5
• Adjuvant impact depends on stage, and there is much room
for improvement6
• Rates of disease recurrence following surgery remain high across
disease stages, regardless of postoperative chemotherapy use7
On December 18, 2020, the FDA approved
osimertinib for adjuvant therapy after tumor
resection in patients with NSCLC whose tumors
have EGFR exon 19 deletions or exon 21 L858R
mutations, as detected by an FDA-approved test
New
Approval
NSCLC 5-Year Overall Survival
Stage I (IB) Stage II Stage III
CALGB
JBR.10
ALPI
IALT
ANITA
LACE
34 57 9
30 7 63
36 60 4
33 65 2
36 60
33 64 3
32 45 23
53 32 15
53 43 4
43 39 18
51 39 10
76 19 5
55 30 15
51 26
61 26 13
23
4
Death (%) with/without chemotherapy
Survival without chemotherapy
Survival due to chemotherapy
Death due to chemotherapy
Localized/early stage
Stage IB Stage II Stage IIIA
Regional/locally advanced

ADAURA: Phase 3 Double-Blind Studya
DFS According to Investigator Assessment10
Patients with completely resected stageb
IB, II, IIIA NSCLC, with or without adjuvant chemoc
Stage I to IIA Disease Stage IB to IIIA Disease
• EGFR TKIs are standard of care for patients with EGFRmut advanced NSCLC
• Previous studies have suggested there may be a role for EGFR TKIs in the resected setting, but results have been inconclusive8,9
• ADAURA: Based on efficacy and safety data, and the new FDA approval, adjuvant osimertinib represents a big opportunity to improve outcomes in more patients
with early-stage NSCLC10
• ≥18 y (Japan/Taiwan, ≥20 y)
• WHO PS 0/1
• Confirmed primary nonsquamous NSCLC
• Ex19del/L858Rd
• Brain imaging, if not completed
preoperatively
• Complete resection with negative marginse
• Maximum interval between surgery and
randomization: 10 wk without adjuvant
chemo; 26 wk with adjuvant chemo
• At 24 mo, 90% of patients treated with osimertinib (95% CI, 84-93) and 44%
of patients treated with placebo (95% CI, 37-51) were alive and disease free
• HR = 0.17; 99.06% CI, 0.11-0.26; P < .001; 83% reduction in risk of disease
recurrence or death
• In the overall population, 89% of patients treated with osimertinib (95% CI, 85-92)
and 52% of patients treated with placebo (95% CI, 46-58) were alive and disease free
at 24 mo
• HR = 0.20; 99.12% CI, 0.11-0.26; P < .001; 80% reduction in risk of disease
recurrence or death
• Primary endpoints: DFS by investigator assessment in stage II/IIIA patients; designed for superiority under the assumed DFS HR of 0.70
• Secondary endpoints: DFS in the overall population;f
DFS at 2, 3, 4, and 5 years; OS; safety; QoL
Osimertinib
90% DFS
Placebo
44% DFS
Stratified by
• Stage (IB vs II vs IIIA)
• EGFRmut (ex19del
vs L858R)
• Race (Asian
vs non-Asian)
Planned treatment duration: 3 y
Treatment continues until
• Disease recurrence
• Treatment completed
• Discontinuation criteria met
Follow-up
• Until recurrence: wk 12 and 24,
then every 24 wk to 5 y, then yearly
• After recurrence: every 24 wk for
5 y, then yearly
Patients
Osimertinib
80 mg, once daily
Placebo
once daily
Osimertinib
89% DFS
Placebo
52% DFS
1:1 randomization

Subgroup HR 95% CI
Overall (N = 682)
Stratified log-rank
Unadjusted Cox PH
0.21
0.20
0.16-0.28
0.14-0.29
Sex
Male (n = 204)
Female (n = 478)
0.21
0.20
0.11-0.38
0.12-0.30
Age
<65 y (n= 380)
≥65 y (n = 302)
0.18
0.24
0.10-0.28
0.14-0.38
Smoking status
Smoker (n = 194)
Nonsmoker (n = 488)
0.14
0.23
0.06-0.27
0.15-0.34
Race
Asian (n = 434)
Non-Asian (n = 248)
0.22
0.17
0.14-0.33
0.08-0.31
Stage
Stage IB (n = 212)
Stage II (n = 236)
Stage IIIA (n = 234)
0.50
0.17
0.12
0.25-0.96
0.08-0.31
0.07-0.20
EGFRmut
Exon 19 deletion (n = 378)
L858R (n = 304)
0.12
0.35
0.07-0.20
0.21-0.55
Adjuvant chemo
Yes (n = 378)
No (n = 304)
0.18
0.23
0.11-0.29
0.13-0.38
0.01 0.1 1.0
Favors osimertinib Favors placebo
HR for DFS (95% CI)
Safety profile was consistent with the established safety profile
of osimertinib, with mild EGFR TKI class effects reported
Consistent improvement in DFS was seen regardless of whether
patients received prior adjuvant chemotherapy
0
0.2
0.4
0.6
0.8
1.0
0 6 12 18 24 30 36 42 48 56
Probability
of
DFS
Time, mo
0
0.2
0.4
0.6
0.8
0 6 12 18 24 30 36 42 48
Probability
of
DFS
Time, mo
Osimertinib
Placebo HR = 0.16 (95%CI, 0.10-0.26)
Osimertinib
Placebo HR = 0.23 (95%CI, 0.13-0.40)
Osimertinib (N = 337), N (%) Placebo (N = 343), N (%)
Adverse Event Any Grade Grade 1 Grade 2 Grade 3 Any Grade Grade 1 Grade 2 Grade 3
Diarrhea 156 (46) 116 (34) 32 (19) 8 (2) 68 (20) 54 (16) 13 (4) 1 (<1)
Paronychia 85 (25) 31 (9) 50 (15) 3 (1) 5 (1) 3 (1) 2 (1) 0
Dry skin 79 (23) 75 (22) 3 (1) 1 (<1) 22 (6) 18 (5) 4 (1) 0
Pruritus 65 (19) 49 (15) 16 (5) 0 30 (9) 28 (8) 2 (1) 0
Cough 62 (18) 43 (13) 19 (6) 0 57 (17) 42 (12) 15 (4) 0
Stomatitis 59 (18) 35 (10) 18 (5) 6 (2) 14 (4) 10 (3) 4 (1) 0
Nasopharyngitis 47 (14) 30 (9) 17 (5) 0 35 (10) 25 (7) 10 (3) 0
Upper respiratory infection 45 (13) 24 (7) 19 (6) 2 (1) 35 (10) 19 (6) 16 (5) 0
Decreased appetite 44 (13) 29 (9) 13 (4) 2 (1) 13 (4) 9 (3) 4 (1) 0
Mouth ulceration 39 (12)
37 (11)
32 (9) 7 (2) 0 8 (2) 6 (2) 2 (1) 0
Dermatitis acneiform 29 (9) 8 (2) 0 16 (5) 12 (3) 4 (1) 0
1.0
Adverse Events10
DFS by Investigator ± Adjuvant Chemo10
CNS DFS by Investigator in the Overall Population10
Subgroup Analysis of DFS by Investigator10
Osimertinib DFS benefit was observed across all predefined subgroups Osimertinib was associated with fewer local/regional and distant
relapses, with a lower incidence of metastatic disease in patients with
recurrence, including fewer CNS recurrence events
HR = 0.18 (95% CI, 0.10-0.33; P < .0001)
Adjuvant osimertinib
demonstrated a clinically
meaningful improvement in
CNS DFS compared
with placebo
82%
reduction
in CNS DFS
Adjuvant osimertinib
is the first targeted agent
to show a statistically
significant and clinically
meaningful improvement
in DFS in patients with
stage IB/II/IIIA EGFRmut
NSCLC10

NeoADAURA: Phase 3 Study11
Selection of Other Trials Assessing Targeted Therapies in Early Stage NSCLC
• Resectable
• Stage II-IIIB NSCLC
• EGFRmut NSCLC
(ex19del/L858R)
Stratification
• Stage I/II
• Non-Asian, Chinese,
other Asian
• Ex19del/L858R
Adjuvant therapy and follow-up
• Patients will be followed for OS until 5 years from
surgery, with evaluation at 12 and 24 weeks post
surgery, then every 23 weeks, until disease
recurrence or withdrawal of consent
• Osimertinib will be offered to all patients who
complete surgery (± post-surgery chemotherapy)
for up to 3 years or until recurrence
Double-blind treatment arms
1. Placebo QD + investigator’s choice of pemetrexed 500 mg/m2
plus
carboplatin AUC 5 mg/mL/min or cisplatin 75 mg/m2
2. Osimertinib 80 mg QD + investigator’s choice of pemetrexed 500 mg/m2
plus carboplatin AUC 5 mg/mL/min or cisplatin 75 mg/m2
Open-label treatment arm
3. Osimertinib 80 mg OD
• Primary endpoint: MPR
• Secondary endpoints: EFS, pathological CR, downstaging (N2 to N1/N0 and N1 to N0 at time of surgery), DFS, OS, MPR in patients with/without EGFRmut,
symptoms, HR-QoL, and safety
• Exploratory endpoints: health resource use using EQ-5D-5L health state utility index, metabolic response per PERCIST, key genetic, gene expression, and
proteomic markers, relationship between molecular evidence of disease and clinical response endpoints, relationship between molecular aberrations and response,
and HLA alleles associated with susceptibility to drug-related AEs
Patients
1:1:1
randomization
N = 351
Placebo + chemotherapy
(3 cycles, Q3W)
Adjuvant
investigator
choice
(optimal care)
Osimertinib + chemotherapy
(3 cycles, Q3W)
Surgery
MPR
& pCR
EFS & OS
Osimertinib (9 weeks)

a
NCT0251106; ADAURA data cutoff: January 17, 2020. b
AJCC, 7th edition. c
Prior, post, and planned radiotherapy was not allowed. d
Centrally confirmed in tissue. e
Patients received a CT after resection and within 28 days before treatment. f
Stage IB/II/IIIA.
1. Datta D, Lahiri B. Chest. 2003;123:2096-2103. 2. Le Chevalier T. Ann Oncol. 2010;21(suppl 7):vii196-vii198. 3. Cagle PT et al. Arch Pathol Lab Med. 2013;137:1191-1198. 4. Chansky K et al. J Thorac Oncol. 2017;12:1109-1121. 5. Postmus PE et al. Ann Oncol. 2017;28(suppl 4):iv1-iv21.
6. Kris MG et al. J Clin Oncol. 2017;35:2960-2974. 7. Pignon J et al. J Clin Oncol. 2008;26:3552-3559. 8. Wu Y-L et al. J Clin Oncol. 2020;38(suppl 15):9005. 9. Huang Q et al. Chest. 2016;149:1384-1392. 10. Wu Y et al. N Engl J Med. 2020;383:1711-1723. 11. https://clinicaltrials.gov/ct2/show/
ecord/NCT04351555.
ALCHEMIST Trials
Selection of Other Trials Assessing Targeted Therapies in Early Stage NSCLC
Stage IB (≥4 cm)-IIIA nonsquamous NSCLC
(N = 6,000-8,000)
Unresectable: off study Complete resection ± adjuvant
treatment with or without radiation
Patients can present before or after
surgery or after adjuvant therapy
Tissue sent to response genetics for EGFR and ALK genotyping
Blood (FF/plasma) sent to NCI CCG
for DNA germline analysis on
patients associated with genomic
research
Advanced Genomics at the NCI
EGFRmut- and ALK-
If recurrence…
EGFRmut+ and/or ALK+
EGFRmut: phase 3
trial of erlotinib vs
placebo x 2 y
(n = 410);
follow up
for 10 y
ALK rearranged:
phase 3 trial of
crizotinib vs
placebo x 2 y
(n = 360);
follow up
for 10 y
Followed on ALCHEMIST screening
to recurrence or every 6 mo x 5 y
Tissue (FFPE) sent to NCI CCG for
genomic research
(deep sequencing, whole exon
sequencing, etc)

Adjuvant EGFR-Targeted Therapy as a Game Changer: How to Implement New Standards of Care in Multimodal Management of Stage I-III EGFR-Mutated NSCLC

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Adjuvant EGFR-Targeted Therapy as a Game Changer: How to Implement New Standards of Care in Multimodal Management of Stage I-III EGFR-Mutated NSCLC