egfr.pptx

EGFR mut NSCLC
BY :
Dr.Bahaa shareef
KHCC
AMMAN JORDAN

Treatment of patients with EGFR mutations
• Where do we stand?
• EGFR mutations present in 10-20% of Caucasian and 40-60% of Asian patients withNSCLC
• 90% of mutations occur in exon 19 (Exon 19del) or exon 21 (L858R)
• EGFR-TKI represent standard of care in patients with EGFR mutations
• Limitation of efficacy by acquired resistance after appr. 12-16 months
• EGFR T790M mutation emerges in 30-60% of patients after treatment with first and second generation EGFR TKIs
• Huge unmet medical need to prolong reponse duration and to overcome resistance
• Current strategies:
• Improvement of TKIs
• Combination with chemotherapies
• Combination with antiangiogenic therapies

Many Options for First-line therapy in EGFRm NSCLC
EGFR mutant NSCLC
Osimertinib
Gefitinib
Erlotinib
Afatinib
Dacomitinib
Erlotinib +
Ramucirumab
Erlotinib +
Bevacizumab
Gefitinib +
Chemotherapy
Is Osimertinib the best single agent as first line?

Many Options for First line therapy in EGFRm NSCLC

1st vs 2nd vs 3rd G EGFR TKI as First-line Therapy
Mok TS et al NEJM 2009, Han JY et al JCO 2012,Maemondo M et al NEJM 2010, Mitsdomi T et al Lancet Oncol 2010, Zhou C et al Lancet Oncol 2011, Rosell R et al Lancet Oncol 2012, Griedell C et al JCO 2012,
Sequist LV et al JCO 2013, Wu YL et al Lancet Oncol 2014, Park K Lancet Oncol 2016, Wu YL Lancet Oncol 2017, JC Soria et al. N Engl J Med 2018Jan 11; 378:113-125
Study Regimen PFS
(months)
HR OS
(months)
HR
IPASS Gefitinib vs carbo/paclitaxel 9.5 vs 6.3 HR=0.48 21.6 vs 21.9 HR=1.0
First-signal Gefitinib vs gemcita/cisplat 8.0 vs 6.3 HR=0.54 27.2 vs 25.6 HR=1.04
NEJ002 Gefitinib vs carbo/paclitaxel 10.8 vs 5.4 HR=0.30 30.5 vs 23.6
WJTOG3405 Gefitinib vs docetaxel/cisplatin 9.2 vs 6.3 HR=0.52 35.5 vs 38.8 HR=1.18
OPTIMAL Erlotinib vs gemcita/cisplatin 13.1 vs 4.6 HR=0.16 22.7 vs 28.9 HR=1.04
EURTAC Erlotinib vs docetaxel/cisplatin 9.7 vs 5.2 HR=0.37 19.3 vs 19.5 HR=1.04
LUX-Lung 3 Afatinib vs pemetrex/cisplatin 13.6 vs 6.9 HR=0.47 28.2 vs 28.2 HR=0.88
LUX-Lung 6 Afatinib vs gemcita/cisplatin 11.0 vs 5.6 HR=0.28 23.1 vs 23.5 HR=0.93
LUX-Lung 7 Afatinib vs gefitinib 11.0 vs 10.9 HR= 0.74 27.9 vs 24.5 HR= 0.86
ARCHER Dacomitinib vs gefitinib 14.7 vs 9.2 HR= 0.59 34.1 vs 26.8 HR= 0.76
FLAURA Osimertinib vs erlotinib/gefitinib 18.9 vs 10.2 HR= 0.46 38.6 vs 31.8 HR= 0.799

Mok. NEJM. 2009;361:947.
IPASS: First-line Gefitinib vs Carboplatin/Paclitaxel in Advanced
NSCLC
• Open-label phase III trial conducted in Asian countries
• Primary endpoint: PFS
• Secondary endpoints: OS, ORR, QoL, symptom reduction, safety
• Biomarker analysis
Previously untreated
patients with stage
IIIB/IV NSCLC,
adenocarcinoma, never
or ex-light smokers,
WHO PS 0-2
(N = 1217)
Gefitinib 250 mg/day PO
(n = 609)
Paclitaxel 200 mg/m2 IV on Day 1 +
Carboplatin AUC 5-6 mg/mL/min IV on Day 1
Up to six 3-wk cycles
(n = 608)

IPASS: PFS
• PFS with gefitinib superior to carboplatin/paclitaxel in ITT population
• EGFR mutations strongly predicted PFS (and tumor response) to
first-line gefitinib vs carboplatin/paclitaxel
Mok. NEJM. 2009;361:947.
EGFR Mutation Positive
HR: 0.48
(95% CI: 0.36-0.64;
P < .001)
Mos Since Randomization
1.0
0.8
0.6
0.4
0.2
0
0 4 8 12 16 20 24
EGFR Mutation Negative
HR: 2.85
(95% CI: 2.05-3.98;
P < .001)
1.0
0.8
0.6
0.4
0.2
0
0 4 8 12 16 20 24
Gefitinib
Carbo/pac
Gefitinib
Carbo/pac
Overall
Probability
of
PFS
HR: 0.74
(95% CI: 0.65-0.85;
P < .001)
1.0
0.8
0.6
0.4
0.2
0
0 4 8 12 16 20 24
Gefitinib
Carbo/pac

First generation vs Second generation EGFR TKI
LUX-Lung 7 ARCHER study
Park K Lancet Oncol 2016, Wu YL Lancet Oncol2017

Park K Lancet Oncol 2016, Wu YL Lancet Oncol2017
PFS PFS

Brain metastases excluded
Lack of adequate CNS penetration
- Randomized phase IIB study -
- Both groups have brain metastasis (16% vs 15%) -
- No OS difference
Park K Lancet Oncol 2016, Mok T JCO 2018
OS OS
27.9m vs 24.5m
34.1m vs 26.8m

Stratification by
mutation status
(Exon 19 deletion /
L858R)
and race
(Asian /
non-Asian)
Crossover was allowed
for patients in the SoC
arm, who could receive
open-label osimertinib
upon central
confirmation of
progression and
T790M positivity
Patients with locally advanced
or metastatic NSCLC
Key inclusion criteria
• ≥18 years*
• WHO performance status 0 / 1
• Exon 19 deletion / L858R
(enrollment by local# or central‡
EGFR testing)
• No prior systemic anti-cancer /
EGFR-TKI therapy
• Stable CNS metastases
allowed
Randomized 1:1
RECIST 1.1 assessment
every 6 weeks¶ until
objective progressive
disease
EGFR-TKI SoC§;
Gefitinib
(250 mg p.o. qd)
or Erlotinib
(150 mg p.o. qd)
(n=277)
TAGRISSO
(80 mg p.o. qd)
(n=279)
Study design
Endpoints
• Primary endpoint: PFS based on investigator assessment (according to RECIST 1.1)
• Secondary endpoints: objective response rate, duration of response, disease control rate, depth of
response, overall survival, patient reported outcomes, safety
JC Soria et al. N Engl J Med 2018 Jan 11; 378:113-125
FLAURA: Osimertinib vs Erlotinib/Gefitinib

PFS in FLAURA

FLAURA: PFS by CNS metastasis at baseline
• CNS progression events occurred in 17 pts (6%) with osimertinib vs 42 pts (15%) with SoC EGFRTKI

Final analysis of Overall Survival of FLAURA
Ramalingam S et al ESMO 2019
• 58% maturity of OS data
• Median OS in osimertinib arm was extended by 6.8 months

Unresolved Issues of Osimertinib as First-line therapy
 Less prominent OS benefit in L858R mutation
 Difference of OS between Asian and Non-Asian
 Mechanism of Resistance and Heterogeneity
 Which sequence has the most significant OS benefit ?

FLAURA: L858R vs Exon 19 del
• Less prominent OS benefit in L858R mutation
PFS OS

FLAURA: OS, Asian vs Non-Asian patients
Median OS 36m vs 36m Median OS 45m vs 24m

FLAURA data cut-off: 12 June 2017; NCT02296125
Crossover was allowed for patients
in the comparator arm, who could
receive open-label osimertinib upon
central confirmation of progression
and T790M positivity
Randomised 1:1
RECIST 1.1 assessment every
6 weeks** until objective
progressive disease
Comparator EGFR-TKI ¶;
Gefitinib (250 mg p.o. qd) or
Erlotinib (150 mg p.o. qd)
(n=277)
Osimertinib
(80 mg p.o. qd)
(n=279)
Plasma samples
taken at baseline
Objective of resistance analysis
• Exploratory analysis of paired pre-treatment and post-treatment plasma samples to investigate mechanisms of acquired resistance to osimertinib in patients who
progressed or discontinued treatment during FLAURA
Stratification by
mutation status
(Exon 19 deletion/
L858R) and race
(Asian/non-Asian)
Patients with locally advanced
or metastatic NSCLC
• ≥18 years*
• WHO performance status 0/1
• Exon 19 deletion/L858R
(enrolment by local# or central‡
EGFR testing)
• No prior systemic anti-cancer/
EGFR-TKI therapy
• Stable CNS metastases were
allowed§
Plasma samples
taken at progression
and/or discontinuation
Ramalingam et al, presented at ESMO 2018
FLAURA study design
Acquired Resistance Mechanism to First-line Osimertinib in pts with EGFR mutation

• No evidence of acquired EGFR T790M
• The most common resistance mechanisms were MET amplification and EGFR C797S mutation
– Other mechanisms include HER2 amplification, PIK3CA and RAS mutations
*Resistance mechanism reported may overlap with another; #Two patients had de novo T790M mut
ations at baseline of whom one acquired C797S at progression
Secondary EGFRmutations:#
C797X: 7%; L718Q+C797S:1%;
L718Q + ex20ins: 1%;S768I: 1%
HER2 amplification:2%
HER2 mutation: 1% MET amplification: 15%
mTOR AKT p53
BIM BCL2
Survival
Apoptosis
PIK3CA
MEK
RAF
RAS
ERK
Proliferation
Fusion ALK
SPTBN1: 1%
HER2
HER2
HER2
HER2
MET
MET
MET
MET
EGFR
EGFR
BRAF mutations (V600E):3%
PIK3CA mutations: 7%
KRAS mutations (G12D/C, A146T):3%
Acquired resistance mechanism with osimertinib (n=91)
Ramalingam et al, presented at ESMO 2018

Afatinib is the most cost effective
Erlotinib is more cost effective than gefitinib
The price of osimertinib should be reduced by 30% to become
cost-effective.

But FLAURA comes with a cost!
Osimertinib: USD 16,000 per month

EGFR mutant NSCLC
Osimertinib
Gefitinib
Erlotinib
Afatinib
Dacomitinib
Erlotinib +
Ramucirumab
Erlotinib +
Bevacizumab
Gefitinib +
Chemotherapy
Should chemotherapy be combined upfront with EGFR TKI?

Planchard ESMO CPG 18 September 2019
EGFR status chemo ORR
MT 47.3%
WT 23.55%

Older trials of chemo+ EGFR TKI were ineffective
but were conducted in unselected population
Study treatment ORR (%) OS (m)
INTACT 1 gefitinib 500mg+ chemo
gefitinib 250mg+ chemo
placebo+ chemo
50.3
51.2
47.2
9.9
9.9
10.9
INTACT 2 gefitinib 500mg+ chemo
gefitinib 250mg+ chemo
placebo+ chemo
30.0
30.4
28.7
8.7
9.8
9.9
TALENT erlotinib + chemo
placebo+ chemo
NR 9.9
10.2
TRIBUTE erlotinib + chemo
placebo+ chemo
21.5
19.3
10.6
10.5

NEJ009
Gefitinib 250 mg/ day
Carboplatin + pemetrexed
Q 21 for 4- 6 cycles
Gefitinib 250 mg OD
1:1
Previously untreated
Advanced non -sq
NSCLC
Up to 75 years old
PS0-1
EGFR mutant
Primary endpoints: PFS,PFS2,and OS
Hosomi et al, JCO 2020
Maintenance
Gefitinib +
Pemetrexed

Combination therapy induces higher ORR and
greater depth of response
Hosomi JCO 2019
Gefitinib + chemo gefitinib
CR 4% 3%
ORR 84% 67% (p<0.01)

Combination therapy confers longer PFS and
longer OS Gefitinib + chemo gefitinib
PFS 20.9m 11.2m
HR 0.49; 95% CI, 0.39- 0.62; p<0.001
OS 50.9m 38.8m
HR 0.72; 95% CI, 0.55 to 0.95; P=0.021
Hosomi JCO 2019

Summary of Adverse Events 
Presented By Atsushi Nakamura at 2018ASCO Annual Meeting

More recent EGFR TKI+
chemotherapy studies: TATA
memorial

Gef vs Gef + C
Presented By Vanita Noronha at 2019ASCO Annual Meeting
Primary endpoint
PFS
Secondary endpoint
OS
Toxicity
Response rate
QOL

Combination therapy induces higher ORR and
greater depth of response
CR 2.9% 0.6%
PR 72.4% 61.9%
SD 12.6% 22.2%
PD 5.2% 6.8%
ORR 75.3% 62.5% (p=0.01)
Depth of response -56.4% -43.5% (p=0.002)
Noronha JCO 2019

Combination therapy confers longer PFS and
longer OS
PFS 16.0m 8.0m
HR 0.51 [95% CI, 0.39- 0.66]; P<0.001
OS NR 17.0m
HR 0.45 [95% CI, 0.31-0.65]; P<0.001
Noronha JCO 2019

Toxicities: increased with combination
Presented By Vanita Noronha at 2019ASCO Annual Meeting

• Stage IIIB–IV NSCLC
• Activating EGFR genomicaberrations
• Performance status ≤1
N=345 Gefitinib
monotherapy
Gefitinib plus
chemotherapy
1:1
• Advanced NSCLC
• Activating EGFR genomicaberrations
• Performance status ≤2
N=350 Gefitinib
monotherapy
Gefitinib plus
chemotherapy
1:1
NEJ0091
Tata2
EGFR-TKI combined with chemotherapy
NEJ009 and Tata Memorial Centre: Study design
Chemotherapy consisted of
pemetrexed and carboplatin
in both trials
EGFR, epidermal growth factor receptor; NSCLC, non-small cell lung cancer; PFS, progression-free survival; TKI, tyrosine kinase inhibitor.
1. Hosomi Y, et al. J Clin Oncol. 2020;38:115–23; 2. Noronha V, et al. J Clin Oncol. 2020;38:124–36.
Pemetrexed
Maintenance
Maintenance
Gefitiniband
pemetrexed
The primary endpoint
for both trials wasPFS

EGFR-TKI combined with chemotherapy
AE, adverse events; EGFR, epidermal growth factor receptor; HR, hazard ratio; NSCLC, non-small cell lung cancer; OS, overall survival; PFS, progression-free survival;
TKI, tyrosine kinase inhibitor.
1. Hosomi Y, et al. J Clin Oncol. 2020;38:115–23; 2. Noronha V, et al. J Clin Oncol.2020;38:124–36.
30
25
20
15
10
5
0
Months
0
5
10
15
20
Months
NEJ0091
Tata2
HR=0.49
p<0.001
HR=0.51
p<0.001
Event
rate
(%)
Median PFS Median OS Grade 3/4 AE
60
50
40
30
20
10
0
Event
rate
(%)
Gefitinib plus chemotherapy
Gefitinib monotherapy
Median OS not
reached for gefitinib
plus chemotherapy
40 40
20 20
0 0
60 60
80 80
Months
HR=0.72
p=0.021

Despite the reservation of adding
chemotherapy to EGFR TKI…
FLAURA2
Janne WCLC2019

Should chemotherapy be
combined upfront with EGFR
TKI?
Yes, if not today, then after FLAURA2!
Osimertinib/ platinum/ pemetrexed
[I, A]

EGFR mutant NSCLC
Osimertinib
Gefitinib
Erlotinib
Afatinib
Dacomitinib
Erlotinib +
Ramucirumab
Erlotinib +
Bevacizumab
Gefitinib +
Chemotherapy
Is a combination of anti-angiogenic with EGFR TKI a new standard?

NEJ026
Saito et al, Lancet Oncology 2019; Maemondo et al, ASCO 2020

NEJ026 –PFS

NEJ026 –Overall Survival

RELAY – Study Design
1. Garon EB et al. Clin Lung Cancer 2017; 2. Reck M et al. Clin Lung Cancer 2018
Treatment until
progression or
unacceptable
toxicity
Ramucirumab 10 mg/kg Q2W
+
Erlotinib 150 mg/day
Placebo Q2W
+
Erlotinib 150 mg/day
Stratification factors
♦ EGFR status (exon 19 deletion vs. exon 21 L858R)
♦ Sex
♦ Region (East Asia vs. other)
♦EGFR testing method (therascreen®/cobas® vs.
other)
•Stage IV NSCLC
•EGFR mutation-positive
(Ex19del or Ex 21
L858R)
•ECOG PS 0-1
Key exclusion criteria
•Known EGFR T790M
mutation
•Prior treatment with
EGFR TKI or
chemotherapy
•Brain metastases
Phase 3a
N=449
aPhase 3 enrollment began after confirmation of dose and schedule in Phase 1b2
Clinicaltrials.gov NCT02411448
Primary end point:
Progression-Free
Survival
R
A
N
D
O
M
I
Z
E
1:1

RELAY: PFS (Investigator assessed)
Nakagawa K et al; Lancet Oncol (2019); 20: 1655-1699
Consistent PFS benefit by independent, blinded central review (HR 0.671, 95% CI, 0.518 – 0.869; p=0.0022)
RAM+ERL
n = 224
PBO+ERL
n= 225
Events 122 158
Median, mo 19.4 12.4
(95% CI) (15.4–21.6) (11.0–13.5)
HR (95% CI) 0.591 (0.461, 0.760)
P-value < 0.0001
1 yr PFS rates:
71.9% vs. 50.7%

RELAY: Subgroup Analyses of PFS
Nakagawa K et al; Lancet Oncol (2019); 20:1655-1699

RELAY – Exploratory Analysis
Nakagawa K et al, ESMO 2020: 1294P
• Superior outcomes in patients with TP53 co
mutation for Ram + Erlotinib in Exon 19 and
Exon 21 mutations
PFS
Exon 19.del: 17.97 vs 9.86 m (HR 0.5)
Exon 21.L858R: 14.65 vs 10.84 (HR 0.56)
• In patients with TP53 wild type tumors
enhanced efficacy for Ram + Erlotinib in
Exon 21 mutations
PFS
Exon 19.del: 20.57 vs 19.35 m (HR 1.00)
Exon 21.L858R: 20.76 vs 13.83 (HR 0.6)

RELAY: PFS2 and Interim OS
RAM+ERL
N=224
PBO+ERL
N=225
PFS2 Events, 61 79
Censoring rate 73% 65%
Median, mo NR NR
HR (95% CI) 0.690 (0.490, 0.972)
Interim OS Events 37 42
Censoring rate 83% 81%
Median, mo NR NR
HR (95% CI) 0.832 (0.532, 1.303)
PFS2 (Investigator-assessed)
PFS2 defined as the time from randomization to 2nd disease progression (defined as objective radiological or symptomatic
progression after start of additional systematic anticancer treatment), or death from any cause, whichever comes first.

RELAY: EGFR T790M Rates Post Progression
♦ Assessed in liquid biopsies by Guardant360 NGS at baseline
and 30-Day follow up
♦ No T790M detected at baseline
♦ Rates shown for patients (n=119) with progression andEGFR
activating mutation (Ex19del or L858R) detected at 30-Day
follow-up
♦ Sensitivity analyses (e.g. not requiring EGFR activating mutation
at 30-Day follow-up) also found no difference between arms
following progression
NGS = Next Generation Sequencing
30-Day FU Post-progression
RAM+ ERL PBO+ERL
T790M (+)/patients with results 19/44 35/75
T790M rates (95% CI)
43
(30, 58)
47
(36, 58)
P-value 0.849

RELAY: Safety
Events %
RAM+ ERL
N= 221
PBO+ ERL N=
225
Any TEAE 100 100
Grade ≥3 TEAEs 72 54
Serious TEAEs 29 21
Discontinued all study treatment due to TEAEs 13 11
Discontinued due to SAE 5 4
TEAEs leading to dose adjustment, any drug 85 71
TEAEs leading to death, on study treatment 1 0

EGFR-TKI combined with anti-VEGF therapy
AE, adverse events; EGFR, epidermal growth factor receptor; EMA, European Medicines Agency; FDA, Food and Drug Administration; HR, hazard ratio;
NSCLC, non-small cell lung cancer; OS, overall survival; PI, product information; PFS, progression-free survival; SPC, summary of product characteristics;
TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor.
1. Saito H, et al. Lancet Oncol. 2019;20:625–35; 2. Maemondon M, et al. J Clin Oncol. 2020;38(15_Suppl):9506; 3. Nakagawa K, et al. Lancet Oncol. 2019;20:1655–69;
4. EMA. Avastin (bevacizumab) infusion, SPC. 2020. Available at: www.ema.europa.eu/en/documents/product-information/avastin-epar-product-information_en.pdf;
5. EMA. Cyramza (ramucirumab) infusion, SPC. 2020. Available at: www.ema.europa.eu/en/documents/product-information/cyramza-epar-product-information_en.pdf;
6. FDA. Cyramza (ramucirumab) injection, PI 2020. Available at: www.accessdata.fda.gov/drugsatfda_docs/label/2020/125477s034lbl.pdf. (PI and SPC accessed 4 Nov 2020).
5
0
20
15
10
Months
25
20
15
10
5
0
Months
NEJ0261,2
RELAY3
HR=0.61
p=0.016
HR=0.59
p<0.0001
0
20
40
25 60
Months
HR=1.00
20
0
80
60
40
100
Event
rate
(%)
Median PFS Median OS Grade 3/4 AE
0
20
40
60
80
Event
rate
(%)
Erlotinib plus bevacizumab
Erlotinib monotherapy
Erlotinib plus ramucirumab
Erlotinib plus placebo
Median OS not
reached for
erlotinib plus
ramucirumab
Approved by EMA for
first-line treatment of
unresectable advanced,
metastatic or recurrent
EGFR-mutant NSCLC4
Approved by EMA and
FDA for first-line
treatment ofmetastatic
EGFR-mutant NSCLC5,6
16.9
vs
13.3
19.4vs12.4

Is a combination of anti-angiogenic
with EGFR TKI a new standard?
• Improvement of PFS for combination of bevacizumab and erlotinib in several trials (without OS benefit)
• Improvement of PFS, DOR and PFS for combination of ramucirumab and erlotinib compared to erlotinib
in RELAY Trial – OS data immature
• Further outcomes from RELAY:
• Efficacy independent from mutation type
• No impact on rates of T790M mutations at progression
• Signal of efficacy in patients with co mutations (TP 53)
• No new safety signals
• Combination trials of ramucirumab with osimertinib ongoing

WJOG8715L Study Design
Key InclusionCriteria
• Advanced lung adeno
carcinoma
• EGFR-TKI resistant
• Acquired EGFRT790M
• ECOG PS 0-1
Stratificationfactors
• Sex
• No. of prior chemotherapy
• Institution
Osi 80 mg/day + Bv 15 mg/kg, q3w
until PD
Lead-in part
(N = 6)
Phase II part
(N = 81)
Osi 80 mg/day + Bv 15 mg/kg, q3w
until PD
Osi 80 mg/dayalone
until PD
 Primary endpoint: PFS by investigator
 Secondary endpoints: overall response rate (ORR), time to treatment
failure (TTF), overall survival (OS) and adverse events (Aes)
R
1 :1

Outcomes of osimertinib and combination therapies
CNS mets ORR PFS (HR) OS (HR) G3+ AE
Monotherapy FLAURA Yes 80% v 76% (ns) 0.46 0.80 34% v 45%
Chemotherapy
combination
NEJ009 Yes 84% v 67% 0.49 0.72 65% v 31%
Tata Memorial Yes 75% v 62% 0.51 0.45 75% v 49%
Anti-angiogenic
combination
NEJ026 Yes 72% v 66% (ns) 0.60 NR 88% v 46%
RELAY No 76% v75% (ns) 0.59 0.83 (ns) 72% v 54%
CTONG 1509 Yes 86% vs 85% (ns) 0.55 NR 53.5% v 25.5%

What would be the Best Sequence?
0 5 25 30 35 (m)
1G/2G EGFR TKI
1G EGFR TKI + Beva or Ramu
Gefitinib + Chemotherapy
Osimertinib
10 15 20
Progression Free Survival
Osimertinib (T790M+) Chemo
Chemo (T790M-)
Chemo (T790M-)
Chemo (T790M-)
Chemo

Do immune checkpoint inhibitors work
in EGFR mutated patients?
Edward B Garon, MD, MS
Professor
Director of Thoracic Oncology Program
David Geffen School of Medicine at UCLA
Director of Signal Transduction and Therapeutics Program
Jonsson Comprehensive Cancer Center at UCLA
September 23, 2020

Trial Design
Planned Enrollment: 25pts
Closed (10/2017): 11pts Enrolled
LisbergA…Garon EB.ASCO 2018, Journal Thoracic Oncology 2018

Efficacy
Figure: Swimmer plot of time on treatment with
reason(s) for treatment discontinuation.
*Adverse event leading to treatmentdiscontinuation.
†Completed treatment and now on surveillance,
still alive at time point of data collection.
‡Death while on erlotinib.
§Subject without EGFR mutation.
Lisberg A….Garon EB. ASCO 2018

OS data in second line immunotherapy

Malignancies with higher mutational load
have been more sensitive
Alexandrov, Nature 2013

Schoenfeld et al. Annals of Oncology2018
Severe immune related adverse events
15% of patients (6 of 41) who received ICI followed by osimertinib developed a severe irAE
No severe irAEs in were found in patients treated with osimertinib followed by ICIs (0 of29)
or ICI followed by other EGFR-TKIs (0 of 27)
Gr. 3 Pneumonitis
Gr. 3 Pneumonitis
Gr. 3 Pneumonitis
Gr. 3 Colitis
Gr. 3 Pneumonitis
Gr. 4 Hepatitis

What about combination ICI + TKI?
Ahn et al., ESMO 2016, TATTON trial
Phase Ib trial of osimertinib and durvalumab was halted due
to toxicity
Interstitial Lung Disease (%)

Socinski MA et al.
N Engl J Med
2018;378:2288-2301

Compared with 212 EGFR wild-type lung cancers,
outcomes with programmed cell death 1 or programmed
death-ligand 1 (PD-(L)1) blockade were worse in patients
with lung tumors harboring alterations in exon 19
of EGFR (EGFRΔ19) but similar for EGFRL858R lung
tumors. EGFRT790M status and PD-L1 expression did
not impact response or survival outcomes to immune
checkpoint blockade. PD-L1 expression was similar
across EGFR alleles. Lung tumors
with EGFRΔ19 alterations harbored a lower tumor
mutation burden compared with EGFRL858R lung tumors
despite similar smoking history.

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