1.
Practice-Changing Developments for Improved
Patient Outcomes in Advanced EGFR Exon 20
Insertion–Mutant NSCLC
Alexander Drilon, MD
Associate Attending Physician, Thoracic Oncology Service
Chief, Early Drug Development Service
Memorial Sloan Kettering Cancer Center

2.
Disclosures
Alexander Drilon, MD
Advisory board/panel: AbbVie, ArcherDX, AstraZeneca, AXIS, BeiGene,
BerGenBio, Blueprint Medicines, Chugai, Elevation Oncology, EMD Serono, EPG
Health, Exelixis, Harborside, Helsinn, Ignyta/Genentech/Roche, Jiangsu Hengrui,
Liberum, Loxo/Bayer/Lilly, MBrace Therapeutics, Melendi, Merus, Monopteros,
MORE Health, Novartis, Nuvalent, Ology Bioservices, Pfizer, Remedica, Repare
Therapeutics, RV Pharma, Takeda/ARIAD/Millennium, Turning Point Therapeutics,
Tyra Biosciences, Verastem
Research support/other financial or material support: Boehringer Ingelheim,
Exelixis, GlaxoSmithKline, Merck, Merus, Pfizer, PharmaMar, Puma, Taiho
Oncology, Teva
i3 Health has mitigated all relevant financial relationships

3.
Learning Objectives
Differentiate predictive and prognostic biomarkers that can guide
individualized management of advanced EGFR exon 20 insertion–
mutant NSCLC
Appraise guideline recommendations for molecular diagnosis in
advanced NSCLC
Evaluate emerging efficacy and safety data on novel selective small
molecule inhibitors for the treatment of advanced EGFR exon 20
insertion–mutant NSCLC
EGFR = epidermal growth factor receptor; NSCLC = non–small cell lung cancer.

4.
EGFR Exon 20 Insertion–Mutant
Lung Cancer:
Scope of the Problem

5.
Lung Cancer Is Driven by Many Actionable Oncogenes
Jordan et al, 2017.

6.
EGFR Exon 20 Mutation
Found in approximately 1% of all NSCLCs
While the exact percentage is small, when multiplied by the global
incidence of lung cancer, the resultant annual worldwide burden is
substantial
Molecular and clinical features will be discussed in detail
Represents an actionable oncogenic driver that can match patients to
targeted therapy
These treatments will be reviewed in this presentation
Yasuda et al, 2012.

7.
EGFR Exon 20 Insertion–Mutant
Lung Cancer: Predictive and
Prognostic Biomarkers

8.
EGFR Mutations Are Grouped Into 3 Major Categories
TK = tyrosine kinase; ATP = adenosine triphosphate; DEL = deletion.
Gazdar & Minna, 2005.
Classical sensitizing
mutations
L858R, exon 19 del
Atypical/uncommon
mutations
G719X, L861Q,
S768I, etc…
Exon 20 mutations

9.
EGFR Exon 20 Alterations Are Heterogeneous
insX = insertion; EX = exon; HER = human epidermal growth factor receptor; ERBB = erythroblastic oncogene B.
Vyse & Huang, 2019; Gazdar & Minna, 2005.
A variety of insertions can
occur at or following the
C-helix of EGFR
These are similar to
HER2/ERBB2 exon 20
insertions

10.
EGFR Exon 20–Mutant Lung
Cancer: Clinical Features

11.
Clinical Features of EGFR Exon 20 Mutations
Arcila et al, 2013; Yasuda et al, 2013; Vyse & Huang, 2019.
Comprise 7%-10% of all EGFR-mutant lung
cancers
≤1% of NSCLC adenocarcinomas in Caucasians
Frequency possibly higher in Asians, for whom
EGFR mutations are more common overall
Many features are shared with other patients
with oncogene-driven lung cancers (eg,
classical EGFR mutations, ALK fusions)
Never smokers, higher proportion of women
Importantly, these features do not define all
patients, and screening should not be biased
solely towards this population

12.
Pathologic and Molecular Features
SVD = D770_N771insSVD; NPH = H773_V774insNPH; FQEA = A763_Y764insFQEA.
Yasuda et al, 2012; Vyse et al, 2019.
Most cancers are lung
adenocarcinomas
Base pair insertions vary (eg,
9 or 12 base pairs,) resulting
in the insertion of a variety of
amino acids (eg, SVD, NPH,
FQEA insertions)
Mutations can involve the C-
helix, near loop, or far loop

13.
EGFR Exon 20–Mutant Lung
Cancer: Diagnosis

14.
Assays That Detect EGFR Exon 20 Mutations
Sabari et al, 2017.
Early efforts focused on single-gene or limited multigene panel testing
Sanger sequencing
Multiplex hotspot mutation testing
Multiplex sizing assays
Contemporary efforts include the interrogation of EGFR exon 20
insertions in addition to other actionable lung cancer drivers
DNA-based and RNA-based next-generation sequencing (NGS)
Comprehensive testing such as this is preferred

15.
Leveraging Plasma in Addition to Tissue Collection
ctDNA = circulating cell-free tumor DNA; CTC = circulating tumor cell; PCR = polymerase chain reaction;
biPAP = bidirectional pyrophosphorolysis-activated polymerization; ddPCR = droplet digital PCR; BEAM = beads, emulsion, amplification, magnetics;
CAPP-Seq = cancer personalized profiling by deep sequencing.
Pantel & Alix-Panabières, 2019.
Plasma circulating tumor DNA testing can
complement tumor-based DNA/RNA testing
for the identification of EGFR exon 20
mutations, along with other actionable
oncogenes

16.
Guidelines for NSCLC Mutation Testing
NCCN guidelines for NSCLC
Strongly advise broad molecular profiling
Molecular testing for EGFR mutations when considering adjuvant TKI
therapy for NSCLC stage IB-IIA
Retesting upon tumor progression
Tissue should be used to diagnose NSCLC
ctDNA can be used in special circumstances
NCCN = National Comprehensive Cancer Network; TKI = tyrosine kinase inhibitor.
NCCN, 2021.
EGFR Exon 20 Mutation

17.
Guidelines for NSCLC Mutation Testing (cont.)
NCCN guidelines for NSCLC
2 major approaches to molecular profiling
Single assays such as NGS identifying EGFR mutations (classical, atypical,
and exon 20), KRAS G12C, BRAF V600E, MET exon 14 skipping,
ALK/ROS1/RET/NTRK1/2/3 fusion, in addition to emerging biomarkers such
as high-level MET amplification and HER2/ERBB2 mutations
Combination of a limited number of assays that identify all of the above: such
a strategy can be limited by tissue availability and the need for repeat
biopsies/testing
Strongly recommend testing for PD-L1 expression level
IHC testing before first-line treatment for metastatic NSCLC
KRAS = Kirsten rat sarcoma virus; BRAF = v-raf murine sarcoma viral oncogene homolog B1; NTRK = neurotrophic tyrosine receptor kinase;
MET = mesenchymal-epithelial transition; PD-L1 = programmed death ligand 1; IHC = immunohistochemical. .
NCCN, 2021.
EGFR Exon 20 Mutation

18.
Case Study 1

19.
Case Study 1: Ms. DS
44-year-old Black woman who never smoked is seen for newly
diagnosed adenocarcinoma involving the lung, lymph nodes, liver, and
bone
Remarkably, despite her extent of disease, she denies disease-related
symptoms (apart from mild fatigue) and has normal kidney and liver
function
A biopsy of a liver metastasis has sufficient tissue for additional testing
after pathologic confirmation

20.
Case Study 1: Ms. DS (cont.)
Which of the following tests is indicated now?
A. Single-gene EGFR mutation testing
B. ALK, ROS1, and RET FISH only
C. Multiplex testing only for driver mutations in lung cancer
D. Next-generation sequencing for multiple actionable alterations
Question 1

21.
Case Study 1: Ms. DS (cont.)
Question 1
Which of the following tests is indicated now?
A. Single-gene EGFR mutation testing
B. ALK, ROS1, and RET FISH only
C. Multiplex testing only for driver mutations in lung cancer
D. Next-generation sequencing for multiple actionable alterations

22.
EGFR Exon 20–Mutant Lung
Cancer: Targeted Therapy
Activity

23.
Older TKI Activity in EGFR Exon 20–Mutant NSCLC
MOS = months; PFS = progression-free survival; PR = partial response; RR = response rate.
Vyse et al, 2019.
Older (eg, first-/second-generation) EGFR TKIs that demonstrated
activity in classical EGFR mutations had no/low/modest activity in
EGFR exon 20 mutations
Agent Mechanism of action Trial Results
Gefitinib/erlotinib EGFR
Retrospective analysis
clinical studies
<3 mos PFS
8%-27% RR
Dacomitinib EGFR/HER2/HER4 NCT00225121
PR for 1 patient with
D770delinsGY
Afatinib EGFR/HER2/HER4
NCT00525148
NCT00949650
NCT01121393
8.7% RR
2.7 mos PFS
Neratinib EGFR/HER2/HER4 NCT00266877 0% RR

24.
Not All Mutant EGFR Proteins Are The Same
Vyse et al, 2019.
The structure of the EGFR
protein with an exon 20 mutation
can differ from that of other
EGFR mutations
This renders it difficult for some
TKIs to inhibit EGFR exon 20
mutants

25.
Poziotinib Activity in EGFR Exon 20–Mutant NSCLC
2 trials examined the activity of poziotinib
ZENITH20: multicenter phase 2 study
Separate single-center study
ORR = objective response rate; MDACC = MD Anderson Cancer Center.
Le et al, 2020.

26.
EGFR Exon 20–Mutant Lung
Cancer: FDA-Approved Targeted
Therapies

27.
Mobocertinib in EGFR Exon 20–Mutant NSCLC
ECOG = Eastern Cooperative Oncology Group; PS = performance status; CIT = checkpoint inhibitor therapy; CNS = central nervous system.
Riely et al, 2021.
Phase 1/2 dose escalation and expansion trial
Mobocertinib 160 mg daily
Characteristic
Patients with EGFR exon 20
insertion (n=28)
Age, median (range), y 62 (28-84)
Sex
Female
Male
21 (75%)
7 (25%)
Race
White
Asian
Black
Other/unknown
20 (71%)
5 (18%)
1 (4%)
2 (7%)
Histology
Adenocarcinoma
Squamous
Large cell
Missing
27 (96%)
0
1 (4%)
0
ECOG PS
0
1
6 (21%)
22 (79%)
Characteristic
Patients with EGFR exon
20 insertion (n=28)
Prior systemic
anticancer regimens
0
1
2
≥3
Unknown
0
4 (14%)
9 (32%)
15 (54%)
0
Type of prior
systemic anticancer
therapy
Chemotherapy
Prior CIT
EGFR/HER2 TKI
28 (100%)
17 (61%)
6 (21%)
History of smoking
Never
Former
Current
Unknown
17 (61%)
11 (39%)
0
0
Baseline CNS metastases 12 (43%)

28.
DOR = duration of response; ASV = V769_D770insASV; IO = immune-oncology therapy.
Riely et al, 2021.
ORR 43%, median DOR 14 months, median PFS 7.3 months
Mobocertinib in EGFR Exon 20–Mutant NSCLC (cont.)

29.
Mobocertinib in EGFR Exon 20–Mutant NSCLC (cont.)
Y = year.
Zhou et al, 2021.
EXCLAIM: phase 1/2
dose escalation/
expansion trial
Mobocertinib 160 mg
daily
PPP: platinum-
pretreated
EXCLAIM cohort:
platinum- and non–
platinum-pretreated
Characteristic PPP (n=114), n (%) EXCLAIM (n=96), n (%)
Age, median (range), y 60 (27-84) 59 (27-80)
Sex
Female
Male
75 (66%)
39 (34%)
62 (65%)
34 (35%)
Race
Asian
Black or African American
White
Not reported
68 (60%)
3 (3%)
42 (37%)
1 (1%)
66 (69%)
2 (2%)
28 (29%)
0
Ethnicity
Hispanic or Latino
Not Hispanic or Latino
113 (99%)
1 (1%)
95 (99%)
1 (1%)
Histologic type
Adenocarcinoma
Squamous
Large cell
112 (98%)
1 (1%)
1 (1%)
95 (99%)
1 (1%)
0
ECOG PS
0
1
29 (25%)
85 (75%)
28 (29%)
68 (71%)
History of smoking
Never
Former
Current
81 (71%)
31 (27%)
2 (2%)
70 (73%)
24 (25%)
2 (2%)
Prior systemic
anticancer regimens
1
2
≥3
47 (41%)
36 (32%)
31 (27%)
49 (51%)
30 (31%)
17 (18%)
Prior systemic anticancer therapy
Platinum-based chemotherapy
Immunotherapy
EGFR TKI
114 (100%)
114 (100%)
49 (43%)
29 (25%)
90 (94%)
86 (90%)
33 (34%)
30 (31%)
Baseline brain metastases 40 (35%) 33 (34%)

30.
IRC = independent review committee; EX20INS = exon 20 insertion; MO = month.
Zhou et al, 2021.
IRC in platinum-pretreated patients: ORR 28%, median DOR 17.5 months,
median PFS 7.3 months
Mobocertinib in EGFR Exon 20–Mutant NSCLC (cont.)

31.
OS = overall survival.
Clinicaltrials.gov, 2019.
EXCLAIM 2 phase 3 trial
First-line trial randomizing patients
Treatment-naive
EGFR exon 20–mutant
advanced NSCLC
Primary outcome:
PFS (IRC)
Secondary outcomes:
ORR, OS
Mobocertinib
Cisplatin/pemetrexed
Carboplatin/pemetrexed
Mobocertinib in EGFR Exon 20–Mutant NSCLC (cont.)

32.
Amivantamab in EGFR Exon 20–Mutant NSCLC
PS = performance status.
Park et al, 2021.
CHRYSALIS: phase 1 dose escalation and expansion
Primary end points: dose-limiting toxicity, overall response rate
Dose: 1,050 mg amivantamab (1,400 mg for ≥80 kg) once weekly for the first 4 weeks and
then once every 2 weeks starting at Week 5
Characteristic
Dose escalation
(n=77), n (%)
Efficacy population
(n=81), n (%)
Median age, years (range) 63 (32-86) 62 (42-84)
Sex
Female
Male
49 (64%)
28 (36%)
48 (59%)
33 (41%)
Race
Asian
White
Black
Not reported
48 (62%)
26 (34%)
3 (4%)
0
40 (49%)
30 (37%)
2 (2%)
9 (11%)
ECOG PS
0
1
2
22 (29%)
55 (71%)
0
26 (32%)
54 (67%)
1 (1%)
Smoking history
Nonsmoker
Smoker
46 (60%)
31 (40%)
43 (53%)
38 (47%)
Median months from initial
diagnosis, (range)
37 (2-173) 17 (1-130)
Characteristic
Dose
escalation
(n=77), n (%)
Efficacy
(n=81), n (%)
NSCLC
subtype
Adenocarcinoma
Squamous cell carcinoma
Others
73 (95%)
3 (4%)
1 (1%)
77 (95%)
3 (4%)
1 (1%)
Median prior lines of therapy (range) 3 (0-10) 2 (1-7)
Previous systemic therapy
Previous platinum-based chemotherapy
Previous immuno-oncology therapy
Previous EGFR TKI
First-generation
Second-generation
Third-generation
Previous exon 20 insertion–targeted
75 (97%)
63 (82%)
29 (38%)
59 (77%)
45 (58%)
15 (20%)
37 (48%)
5 (7%)
81 (100%)
81 (100%)
37 (46%)
20 (25%)
7 (9%)
6 (7%)
6 (7%)
1 (1%)
No previous therapy 2 (3%) 0%

33.
Amivantamab in EGFR Exon 20–Mutant NSCLC (cont.)
SOD = sum of lesion diameter; CBR = clinical benefit rate.
Park et al, 2021.
ORR 40%
Median DOR
11.1 months
Median PFS 8.3
months

34.
Amivantamab in EGFR Exon 20–Mutant NSCLC (cont.)
CR = complete response; NE = not estimable; UNK = unknown.
Park et al, 2021.

35.
Case Study 2

36.
Case Study 2: Ms. ML
58-year-old woman who was diagnosed with a stage IV metastatic non–
small cell carcinoma involving the lungs, lymph nodes, and brain
She initially received carboplatin, pemetrexed, and pembrolizumab, followed
by maintenance pemetrexed and pembrolizumab
During this time, sequencing identified an EGFR exon 20 mutation, but
targeted therapy was reserved for progression
Current scans show new liver metastases and growing lung metastases

37.
Case Study 2: Ms. ML (cont.)
What do you do next?
A. Start amivantamab
B. Add carboplatin back to pemetrexed and pembrolizumab
C. Request PD-L1 testing that was not previously performed
D. Start osimertinib
PD-L1 = programmed death ligand 1.
Question 1

38.
Case Study 2: Ms. ML (cont.)
What do you do next?
A. Start amivantamab
B. Add carboplatin back to pemetrexed and pembrolizumab
C. Request PD-L1 testing that was not previously performed
D. Start osimertinib
Question 1

39.
Case Study 2: Ms. ML (cont.)
Amivantamab was approved for administration
The patient is cleared for her first infusion

40.
EGFR Exon 20–Mutant Lung
Cancer: Targeted Therapy
Safety

41.
Poziotinib Safety in EGFR Exon 20–Mutant NSCLC
TRAE = treatment-related adverse event.
Le et al, 2020.
Treatment-related AE
(N=115)
Any grade
n (%)
Grade 3
n (%)
Grade 4
n (%)
Any TRAE 114 (99%) 70 (61%) 2 (2%)
Diarrhea 91 (79%) 29 (25%) 1 (1%)
Rash 69 (60%) 32 (28%) 0%
Stomatitis 60 (52%) 10 (9%) 0%
Paronychia 52 (45%) 7 (6%) 0%
Nausea 44 (38%) 3 (3%) 0%
Decreased appetite 36 (31%) 2 (2%) 0%
Mucosal inflammation 34 (30%) 8 (7%) 0%
Dry skin 33 (29%) 3 (3%) 0%
Vomiting 33 (29%) 1 (1%) 0%
Alopecia 31 (27%) 0% 0%
Dermatitis acneiform 30 (26%) 8 (7%) 1 (1%)
Fatigue 30 (26%) 6 (5%) 0%
Pruritus 29 (25%) 5 (4%) 0%

42.
Mobocertinib Safety in EGFR Exon 20–Mutant NSCLC
D = day;
GERD = gastroesophageal
reflux disease.
Riely et al, 2021.
Patients with EGFR exon 20 insertion
mutations treated at 160 mg/d (n=28)
All patients treated at 160 mg/d (n=136)
TEAE Any grade Grade ≥3 Any grade Grade ≥3
Diarrhea 23 (82%) 9 (32%) 113 (83%) 28 (21%)
Nausea 11 (39%) 3 (11%) 58 (43%) 5 (4%)
Rash 13 (46%) 0% 45 (33%) 1 (1%)
Vomiting 10 (36%) 2 (7%) 36 (26%) 5 (4%)
Dry skin 5 (18%) 0% 30 (22%) 0%
Decreased appetite 11 (39%) 0% 29 (21%) 1 (1%)
Stomatitis 6 (21%) 2 (7%) 28 (21%) 5 (4%)
Fatigue 4 (14%) 1 (4%) 28 (21%) 2 (1%)
Rash maculopapular 7 (25%) 1 (4%) 22 (16%) 1 (1%)
Paronychia 8 (29%) 0% 22 (16%) 0%
Anemia 5 (18%) 0% 19 (14%) 3 (2%)
Dermatitis acneiform 5 (18%) 0% 19 (14%) 1 (1%)
GERD 3 (11%) 0% 17 (13%) 0%
Dyspepsia 6 (21%) 0% 16 (12%) 0%
Increased lipase 7 (25%) 2 (7%) 15 (11%) 7 (5%)
Pruritus 5 (18%) 0% 14 (10%) 0%

43.
Amivantamab Safety in EGFR Exon 20–Mutant NSCLC
AE = adverse event; RP2D = recommended phase 2 dose; ALT = alanine aminotransferase.
Park et al, 2021.
Safety population (n=114), n (%) Patients treated at the RP2D (n=258), n (%)
Most common AE (≥10%) Total Grade 1 Grade 2 Grade ≥3 Total Grade 1 Grade 2 Grade ≥3
Rash 98 (86%) 43 (38%) 51 (45%) 4 (4%) 202 (78%) 101 (39%) 94 (36%) 7 (3%)
Infusion-related reaction 75 (66%) 9 (8%) 63 (55%) 3 (3%) 167 (65%) 21 (8%) 140 (54%) 6 (2%)
Paronychia 51 (45%) 28 (25%) 22 (19%) 1 (1%) 104 (40%) 50 (19%) 51 (20%) 3 (1%)
Hypoalbuminemia 31 (27%) 6 (5%) 22 (19%) 3 (3%) 63 (24%) 21 (8%) 38 (15%) 4 (2%)
Constipation 27 (24%) 18 (16%) 9 (8%) 0% 58 (23%) 36 (14%) 22 (9%) 0%
Nausea 22 (19%) 17 (15%) 5 (4%) 0% 55 (21%) 40 (16%) 14 (5%) 1 (0.4%)
Dyspnea 22 (19%) 12 (11%) 8 (7%) 2 (2%) 52 (20%) 28 (11%) 13 (5%) 11 (4%)
Stomatitis 24 (21%) 11 (10%) 13 (11%) 0% 50 (19%) 33 (13%) 17 (7%) 0%
Peripheral edema 21 (18%) 20 (18%) 1 (1%) 0% 50 (19%) 43 (17%) 5 (2%) 2 (1%)
Pruritus 19 (17%) 11 (10%) 8 (7%) 0% 49 (19%) 40 (16%) 9 (4%) 0%
Fatigue 21 (18%) 15 (13%) 4 (4%) 2 (2%) 47 (18%) 29 (11%) 16 (6%) 2 (1%)
Cough 16 (14%) 11 (10%) 5 (4%) 0% 40 (16%) 25 (10%) 15 (6%) 0%
Decreased appetite 16 (14%) 7 (6%) 9 (8%) 0% 39 (15%) 23 (9%) 16 (6%) 0%
Dry skin 18 (16%) 18 (16%) 0% 0% 33 (13%) 32 (12%) 1 (0.4%) 0%
Increased ALT 17 (15%) 15 (13%) 1 (1%) 1 (1%) 30 (12%) 22 (9%) 5 (2%) 3 (1%)

44.
Case Study 2 (cont.)

45.
Case Study 2: Ms. ML (cont.)
Which of the following is NOT expected with therapy?
A. The patient will need to return on Day 2 for additional treatment
B. The patient may experience an infusion reaction
C. The patient has a high likelihood of experiencing light-dark adaptation
problems
D. The patient may experience nail changes
Question 2

46.
Case Study 2: Ms. ML (cont.)
Question 2
Which of the following is NOT expected with therapy?
A. The patient will need to return on Day 2 for additional treatment
B. The patient may experience an infusion reaction
C. The patient has a high likelihood of experiencing light-dark
adaptation problems
D. The patient may experience nail changes

47.
EGFR Exon 20–Mutant Lung
Cancer: Management Algorithm

48.
Managing EGFR Exon 20–Mutant NSCLC
NCCN, 2021.
EGFR exon
20 insertion
mutation–
positive
Systemic therapy
for
adenocarcinoma
or squamous cell
carcinoma
Tumor
response
evaluation
Progression
Amivantamab
or
mobocertinib
Progression
If not received
previously,
amivantamab or
mobocertinib or
systemic therapy
Systemic
therapy
Response
or stable
disease
4-6
cycles
total
Tumor
response
evaluation
Progression
Amivantamab-vmjw
or mobocertinib
Progression
Response or
stable
disease
Maintenance
therapy
Progression
Amivantamab or
mobocertinib

49.
EGFR Exon 20–Mutant Lung
Cancer: First-Line Therapy and
Maintenance

50.
PD-L1 expression–
positive (≥1%-49%),
negative
for actionable
molecular markers,
and no
contraindications
to PD-1 or PD-L1
inhibitors
aAll recommendations are category 1 unless otherwise specified.
NOS = not otherwise specified.
NCCN, 2021.
PD-L1 Expression–Positive (≥1%-49%)
Current Treatment Strategy of NSCLC
Preferred
(Carboplatin or cisplatin)/pemetrexed/
pembrolizumab
Other recommended
Carboplatin/paclitaxel/
bevacizumab/atezolizumab or
Carboplatin/albumin-bound paclitaxel/
atezolizumab or
Nivolumab/ipilimumab/pemetrexed/
(carboplatin or cisplatin)
Useful in certain circumstances
Nivolumab/ipilimumab or
Pembrolizumab (category 2B)
Preferred
Carboplatin/(paclitaxel or albumin-
bound paclitaxel)/pembrolizumab
Other recommended
Nivolumab/ipilimumab/paclitaxel/
carboplatin
Useful in certain circumstances
Nivolumab/ipilimumab or
Pembrolizumab (category 2B)
PS 0-2
Adenocarcinoma,
large cell, NSCLC NOS
Squamous cell carcinoma
Response or stable
disease
Progression
Continuation maintenance
Pembrolizumab
Pembrolizumab/pemetrexed
Atezolizumab and bevacizumab
Atezolizumab
Nivolumab/ipilimumab
Systemic therapy or
Subsequent therapy
Response or stable
disease
Progression
Continuation maintenance
Pembrolizumab
Nivolumab/ipilimumab
Systemic therapy or
Subsequent therapy
First-Line Therapya

51.
PD-L1 expression–
positive (≥50%),
negative for
actionable
molecular markers,
and no
contraindications
to PD-1 or PD-L1
inhibitors
aAll recommendations are category 1 unless otherwise specified.
NCCN, 2021.
PD-L1 Expression–Positive (≥50%)
Current Treatment Strategy of NSCLC (cont.)
Preferred
Pembrolizumab or
(Carboplatin or cisplatin)/
pemetrexed/pembrolizumab or
Atezolizumab or
Cemiplimab-rwlc
Other recommended
Carboplatin/paclitaxel/bevacizumab/
atezolizumab or
Carboplatin/albumin-bound paclitaxel/
atezolizumab or
Nivolumab/ipilimumab/pemetrexed/
(carboplatin or cisplatin)
Useful in certain circumstances
Nivolumab/ipilimumab
Preferred
Pembrolizumab or
Carboplatin/(paclitaxel or albumin-bound
paclitaxel)/pembrolizumab or
Atezolizumab or
Cemiplimab-rwlc
Other recommended
Nivolumab/ipilimumab/paclitaxel/carboplatin
Useful in certain circumstances
Nivolumab/ipilimumab
PS 0-2
Adenocarcinoma,
large cell, NSCLC NOS
Squamous cell carcinoma
Response or stable
disease
Progression
First-Line Therapya
Continuation maintenance
Pembrolizumab (category 1)
Pembrolizumab/pemetrexed
(category 1)
Atezolizumab and bevacizumab
(category 1)
Atezolizumab
Nivolumab/ipilimumab
(category 1)
Cemiplimab-rwlc (category 1)
Systemic therapy or
Subsequent therapy
Response or stable
disease
Progression
Continuation maintenance
Pembrolizumab (category 1)
Atezolizumab
Nivolumab/ipilimumab (category 1)
Cemiplimab-rwlc (category 1)
Systemic therapy or
Subsequent therapy

52.
Case Study 2 (cont.)

53.
Case Study 2: Ms. ML (cont.)
After 10 months on therapy with substantial disease control, further
disease progression is observed
The patient remains fit and with good organ function

54.
Case Study 2: Ms. ML (cont.)
Which of the following is the least reasonable next step?
A. Restarting pembrolizumab
B. Initiating mobocertinib
C. Considering docetaxel and ramucirumab
D. Clinical trial
gem = gemcitabine; carbo = carboplatin.

55.
Case Study 2: Ms. ML (cont.)
Which of the following is the least reasonable next step?
A. Restarting pembrolizumab
B. Initiating mobocertinib
C. Considering docetaxel and ramucirumab
D. Clinical trial

56.
EGFR Exon 20–Mutant Lung
Cancer: Summary

57.
Key Takeaways
EGFR exon 20 mutations are found in approximately 1% of non–small
cell lung cancers. These drivers are clinically actionable
Diagnosis should be made with a comprehensive assay that identifies
these mutations in addition to other actionable oncogenes
Targeted therapy is active. Many agents have been explored, and 2
are approved:
Mobocertinib
Amivantamab

58.
References
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