Abramson Cancer Center University of Pennsylvania Philadelphia Pennsylvania Keeping Up in NSCLC Actionable Biomarkers and Their Impact on Treatment Rasheda Persinger MSN AGNPC AOCNP Lead Nurse Practitioner ID: 932352
Download Presentation The PPT/PDF document "Beth Sandy, MSN, CRNP Nurse Practitioner" is the property of its rightful owner. Permission is granted to download and print the materials on this web site for personal, non-commercial use only, and to display it on your personal computer provided you do not modify the materials and that you retain all copyright notices contained in the materials. By downloading content from our website, you accept the terms of this agreement.
Slide1
Slide2Beth Sandy, MSN, CRNP
Nurse PractitionerAbramson Cancer Center University of PennsylvaniaPhiladelphia, Pennsylvania
Keeping Up in NSCLC: Actionable Biomarkers and Their Impact on Treatment
Rasheda Persinger, MSN, AGNP-C, AOCNP
Lead Nurse Practitioner
Division of Medical Oncology
Johns Hopkins University
Washington, DC
Slide3Please feel free to use and share some or all of these slides in your noncommercial presentations to colleagues or patients
When using our slides, please retain the source attribution:These slides may not be published, posted online, or used in commercial presentations without permission. Please contact pce@practicingclinicians.com for details
About These Slides
3
Slide credit:
practicingclinicians.com
:
Slide4Beth Sandy, MSN, CRNP:
consultant: Amgen, AstraZeneca, Janssen, Jazz, Merck, Takeda.Rasheda Persinger, MSN, AGNP-C, AOCNP: consultant/advisor/speaker: AstraZeneca, Guardant Health, Pfizer.Faculty and Content Development Disclosures
4
Slide credit:
practicingclinicians.com
:
Slide5Identify actionable biomarkers in non-small-cell lung cancer (NSCLC)
Describe guideline-recommended testing strategies for NSCLC Develop treatment strategies based on actionable biomarkers in patients with NSCLC Learning Objectives5Slide credit: practicingclinicians.com:
Slide6Lung cancer is one of the most common cancers and is the leading cause of cancer deaths in the US and worldwide
New cases: US, 236,740 estimated in 2022; global, 1.8 million in 2012Deaths: US, 130,180 estimated in 2022; global, 1.7 million in 20155-year US survival ratesOverall: 22.9%Metastatic: 7.0%NSCLC accounts for between 80% and 85% of lung cancersLung Cancer Remains Major Global Health Burden
seer.cancer.gov/
statfacts
/html/lungb.html.
Siegel. CA Cancer J Clin. 2022;72:7. American Cancer Society. What is
l
ung
cancer?
6
Slide credit:
practicingclinicians.com
:
Slide7Molecular and PD-L1 Testing at Initial Diagnosis to Guide Treatment in NSCLC
Initial Diagnosis of NSCLC
Advanced
Early Stage
Targetable alteration
PRESENT
No targetable alteration
Matched targeted therapy
PD-L1 low (1%-49%)
or neg (<1%)
PD-L1 high
(≥50%)
Molecular testing and PD-L1 IHC
EGFR
(classical) mutation PRESENT, stage IB-IIIA
PD-L1 IHC ≥1%,
stage II-IIIA
± Chemo →
osimertinib
Chemo →
atezolizumab
Adjuvant:
Molecular testing (EGFR) and PD-L1 IHC following surgical resection
Regardless of
PD-L1 status,
tumors ≥4 cm or N+
Platinum-doublet
c
hemo +
nivolumab
Neoadjuvant:
No molecular testing or
PD-L1 IHC required
7
Slide credit:
practicingclinicians.com
:
Slide8Approximately 50% of Patients With Advanced Nonsquamous NSCLC Have a Driver Mutation Targetable By an FDA-Approved Agent
*Approved in combination with trametinib (MEK inhibitor) for the
BRAF
V600E mutation.
Tsao. J Thorac Oncol. 2016;11:613.
Skoulidis
. Nat Rev Cancer. 2019;19:495.
ALK
7%
EGFR
Other 4%
MET
3%
>1 Mutation 3%
HER2
2%
ROS1
2%
RET
2%
NTRK1
1%
PIK3CA
1%
MEK1
<1%
BRAF
2%
Unknown Oncogenic Driver Detected 31%
KRAS
25%
(KRAS
G12C
13%)
EGFR
Sensitizing
17%
ALK
7%
ROS1
:
Crizotinib
Entrectinib
BRAF
V600E:
Dabrafenib*
NTRK
fusion:
Entrectinib
Larotrectinib
MET
ex14:
Capmatinib Tepotinib
RET
fusion:
Selpercatinib
Pralsetinib
ALK
:
Crizotinib
Alectinib
Ceritinib
Lorlatinib
Brigatinib
EGFR
Sensitizing:
Gefitinib
Erlotinib
Afatinib
Osimertinib
Dacomitinib
KRAS
G12C
:
Sotorasib
EGFRex20
:
Amivantamab
Mobocertinib
8
Slide credit:
practicingclinicians.com
:
Slide9NCCN = National Comprehensive Cancer Network; OS = overall survival.
Singal. JAMA. 2019;321:1391.We know from many studies that patients who get chemotherapy as opposed to the targeted therapy specific to their driver mutation do much worse
Why Do We Perform Biomarker Testing in NSCLC?
11.4
mo
OS: standard chemotherapy when they had a driver mutation
18.6
mo
OS: targeted therapy for their driver mutation
OS by Receipt of Guideline Recommended Therapy
Received NCCN therapy (n = 575)
Did not receive NCCN therapy (n = 560)
Time (
mo
)
Survival Probability
0
10
20
30
40
50
0
0.25
0.50
0.75
1.00
P
<.001
9
Slide credit:
practicingclinicians.com
:
Slide10Robert. ASCO 2021. Abstract 9004.
N = 3474 patients in US Oncology Network (2018-2020)Adenocarcinoma: 75%But Are We Testing?! The MYLUNG CONSORTIUM Data
Test Types
Overall
(N = 3474), %
Nonsquamous
(N = 2820), %
EGFR
70
76
ALK
70
76
ROS1
68
73
BRAF
55
59
PD-L1
83
83
Any biomarker
90
91
All 5 biomarker tests
46
49
NGS
37
39
10
Slide credit:
practicingclinicians.com
:
Slide11Biomarker Testing in Advanced NSCLC
Nonsquamous*EGFR
mutations/alterations/insertions
ALK
rearrangements
ROS1
rearrangements
BRAF
V600E mutations
MET
exon 14 skipping mutations
RET
fusions
NTRK
fusions
KRAS
mutations
Recommended that above be done as part of broad molecular testing by NGS to use the least amount of tissue
PD-L1 by IHC
Squamous
Consider molecular testing
Recommended that above be done as part of broad molecular testing by NGS to use the least amount of tissue
PD-L1 by IHC
*Including adenocarcinoma, large cell, NSCLC not otherwise specified.
www.nccn.org
. Pennell. ASCO Educ Book. 2019;39:351.
11
Slide credit:
practicingclinicians.com
:
Slide12Biomarker Testing in Advanced NSCLC
Nonsquamous*EGFR
mutations/alterations/insertions
ALK
rearrangements
ROS1
rearrangements
BRAF
V600E mutations
MET
exon 14 skipping mutations
RET
fusions
NTRK
fusions
KRAS
mutations
Recommended that above be done as part of broad molecular testing by NGS to use the least amount of tissue
PD-L1 by IHC
Squamous
Consider molecular testing
Recommended that above be done as part of broad molecular testing by NGS to use the least amount of tissue
PD-L1 by IHC
*Including adenocarcinoma, large cell, NSCLC not otherwise specified.
www.nccn.org
. Pennell. ASCO Educ Book. 2019;39:351.
12
ACTION ITEM:
Order biomarker testing, preferably NGS, to identify actionable mutations in all patients with advanced
nonsquamous
NSCLC; consider in squamous NSCLC
Slide credit:
practicingclinicians.com
:
Slide13Hahn.
Oncotarget. 2017;8:33614. Leighl. Clin Cancer Res. 2019;25:4691. Lindeman. J Thorac Oncol. 2013;8:823. Pennell. ASCO Educ Book. 2019;39:531. www.nccn.org. Tissue from the primary tumor or metastatic site equally suitableBone biopsy potentially suboptimal due to decalcification and degradation of DNA, but new methodologies are evolvingLiquid biopsies (cell-free DNA in plasma) are another option13Biopsy for Biomarker TestingSlide credit:
practicingclinicians.com:
Slide14Blood sample containing cell-free (
cf) DNA from multiple sources, including DNA shed from tumorLiquid BiopsyWhen do we use liquid biopsy?Plasma-first approach:
for inadequate or no tissue biopsy—if negative, rebiopsy for tumor tissueSequential approach
:
tumor tissue adequate for genotyping—follow with cfDNA testing only when results from tissue incomplete
Complementary approach
:
increases rate of biomarker detection
Resistance to TKIs
Advantages:
minimally invasive, may overcome
tumor heterogeneity
Limitations:
Sensitivity (70%-80%), specificity near 100%; negative result is noninformative; cannot assess histology or PD-L1
CTC = circulating tumor cell.
Bauml. Clin Cancer Res. 2018;24:4352.
Leighl
. Clin Cancer Res. 2019;25:4691. Rothwell. Nat Med. 2019;25:738.
Figure 1 of Lowes. Int J Mol Sci. 2016:17:E1505 is used in its original form under the terms and conditions of the Creative Commons Attribution 4.0 International license (CC BY 4.0: https://creativecommons.org/licenses/by/4.0/).
14
Slide credit:
practicingclinicians.com
:
Slide152022 Treatment Paradigm for Molecular Biomarker–Positive Advanced NSCLC
Advanced NSCLC
(molecular biomarker positive)
*Osimertinib also approved as second-line therapy for
EGFR
T790M–positive disease after an earlier-generation EGFR TKI.
†
Afatinib
, dacomitinib, erlotinib (alone or in combination with ramucirumab), gefitinib, and
osimertinib
approved for
EGFR
exon19del, exon 21 L858R; erlotinib, gefitinib, and dacomitinib also options for
EGFR
G719X, S768I, L861Q.
‡
Or as second-line after CT. ^
Crizotinib
also an option for
MET
ex14 skipping mutation.
Afatinib
PI.
Alectinib
PI.
Amivantamab
PI.
Capmatinib
PI.
Ceritinib
PI.
Crizotinib
PI. Dabrafenib PI. Dacomitinib PI.
Entrectinib
PI. Erlotinib PI. Gefitinib PI.
Lorlatinib
PI. Larotrectinib PI.
Mobocertinib
PI. Osimertinib PI.
Pralsetinib PI. Selpercatinib PI. Sotorasib
PI. Trametinib PI. NCCN Clinical Practice Guidelines
in Oncology: NSCLC (v3.2022)
ALK
Progression
EGFR
ROS1
Crizotinib
or
entrectinib
Follow treatment options for adenocarcinoma or squamous cell carcinoma without actionable biomarker (
ie
, chemotherapy ± immunotherapy)
Alectinib,
brigatinib, ceritinib, or lorlatinib dependent on previous therapy
Alectinib
,
brigatinib
,
lorlatinib
(preferred),
ceritinib
, or
crizotinib
‡
Osimertinib (preferred)*, erlotinib, afatinib, gefitinib, or dacomitinib
†
BRAF
V600E
Dabrafenib/
trametinib
†
First line
Second line and beyond
Entrectinib
or
larotrectinib
NTRK
Selpercatinib
or
pralsetinib
RET
Capmatinib
or
Tepotinib
^
MET
ex14
skipping
KRAS
G12C
Sotorasib
Classical
(
del19 or
L858R)
Uncommon
ex20ins
Uncommon
(S768I, L861Q, G719X)
Amivantamab
or
mobocertinib
Afatinib
or
osimertinib
(preferred)
†
15
Slide credit: practicingclinicians.com:
Slide16More common (but not exclusively)
Never/minimal smokers, East Asians, Women
Classical mutations make up majority
Exon 19del
Exon 21point/L858R
Atypical/uncommon EGFR mutations
Including G719X, L861Q, S768I
Some are sensitive to traditional EGFR inhibitors
More study needed
EGFR Mutations in NSCLC: Overview
Exon 20 insertions
Resistant to traditional EGFR inhibitors
New drugs approved
Sehgal. Oncologist. 2021;26:281.
Uncommon
EGFR
mutations in NSCLC
Others – 0.9%
Exon 19 del
44.2%
L858R
31.3%
Exon 20 ins
12.8%
G719X
6.1%
S768I
2.4%
L861Q
2.4%
16
Slide credit:
practicingclinicians.com
:
Slide17*P
= 0.046. †P = 0.043. CT = chemotherapy; mNSCLC = metastatic non-small-cell lung cancer. Afatinib PI. Dacomitinib PI. Erlotinib PI. Gefitinib PI. Inoue. Ann Oncol. 2013;24:54. Mok. J Clin Oncol. 2018;36:2244. Osimertinib PI. Ramalingam. N Engl J Med. 2020;382:41. Sholl. Transl Lung Cancer Res. 2017;6:560. www.nccn.org.
Drug
OS in
First
L
ine
(comparator)
FDA
Indication(s)
Gefitinib
(1st generation)
HR: 0.89,
95% CI: 0.63-1.24
(CT)
1
st
line
mNSCLC
with L858R
or exon19del
Erlotinib
(1st generation)
HR: 0.93, 95% CI: 0.64-1.35 (CT)
1
st
line
mNSCLC
with L858R or exon19del
2
nd line
after progression with CT
Afatinib
HR: 0.88
, 95% CI: 0.66-1.87 (CT)
1
st line mNSCLC
with nonresistant EGFR mutations
2nd line in metastatic squamous NSCLC after CT
Osimertinib
HR: 0.80, 95% CI: 0.64-1.00*
1st line mNSCLC with L858R or exon19delSubsequent line mNSCLC with EGFR
T790M mutation after progression on TKI
Dacomitinib
HR: 0.76, 95% CI:
0.58-0.99
†
(gefitinib
)
1
st
line mNSCLC
with L858R or exon19del
Biomarker-Directed Therapy:
EGFR
Classical Mutations
17
Slide credit:
practicingclinicians.com
:
Slide18CNS = central nervous system; PFS = progression-free survival.
Ramalingam. N Engl J Med. 2020;382:41. Soria. N Engl J Med. 2018;378:113. Osimertinib improved OS and PFS in overall patient cohort vs gefitinib or erlotinibOS: HR 0.80, 95% CI: 0.64-1.00; P = 0.046PFS: HR 0.46, 95% CI: 0.37-0.57; P <0.001Known to have good CNS penetrationReduced risk of progression by ~53%, with or without baseline CNS metastasesFLAURA: Osimertinib vs First-Generation TKIs Improved PFS for Patients With Advanced EGFR+ NSCLC and CNS Metastases
PFS in Patients With CNS Metastasis
15.2 (12.1-21.4)
9.6 (7.0-12.4)
Median PFS,
Mo (95% CI)
Standard EGFR-TKI
53
63
No. of
Patients
HR for disease progression
or death,
0.47 (95% CI: 0.30-0.74)
P <0.001
1.0
0.8
0.6
0.4
0.2
0
0
3
6
9
12
15
18
21
24
27
Probability of
PFS
Mo
Osimertinib
18
Slide credit:
practicingclinicians.com
:
Slide19Phase III ADAURA Trial: Adjuvant Osimertinib for
Early-Stage EGFR-Mutated NSCLC
DFS = disease-free survival; IDMC = independent data monitoring committee.
Wu. NEJM. 2020;383:1711. Osimertinib PI.
Patients at Risk, n
Osimertinib
Placebo
339 313 272 208 138 74 27 5 0
343 287 207 148 88 53 20 3 1
Probability of DFS
Months From Randomization
1.0
0.8
0.6
0.4
0.2
0
0
6
12
18
24
20
36
42
48
DFS in Overall Population (Stage IB/II/IIIA)
HR:
0.20 (99.12% CI: 0.14-0.30;
P
<.001)
Osimertinib
Placebo
Median DFS,
M
o
NR
27.5
International, randomized, double-blind phase III trial (data cutoff for interim analysis: 1/17/2020)
IDMC recommended early unblinding due to efficacy
-
DFS benefit with
osimertinib
seen across subgroups
FDA approved in December 2020 for adjuvant treatment of adults with stage IB-IIIA
EGFR+
(del19 or L585R) NSCLC following tumor resection ± adjuvant CT
19
Slide credit:
practicingclinicians.com
:
Slide20*Reported by >20% of patients receiving TKIs in clinical trials.
Afatinib PI. Dacomitinib PI. Erlotinib PI. Gefitinib PI. Osimertinib PI. EGFR TKIs: Dosing and Side EffectsDrug
Dosage
and
Administration
Frequent Side
Effect
s (>20%)*
Grade ≥3 Side Effects (≥2%)
Erlotinib
150 mg
daily
on
empty stomach
Diarrhea, rash, anorexia
, fatigue, dyspnea, cough, nausea, vomiting
Rash (14%), dyspnea (8%), diarrhea (5%), back pain (2%)
Gefitinib
250 mg daily with or without food
Diarrhea, skin reactions (dermatitis,
dry skin, rashes, pruritus)
Diarrhea
(3%), decreased appetite (2.3%), s
kin
reactions (2%)
Afatinib
40 mg daily,
1 hour before
or 2 hours after meal
Diarrhea, dermatitis, stomatitis, paronychia, dry skin, decreased
appetite, nausea, vomiting, pruritus
Dermatitis (16%),
d
iarrhea (15%),
paronychia (11%),
stomatitis (9%)
Osimertinib
80 mg daily
with or without food
Diarrhea, rash, dry skin, nail toxicity,
stomatitis, fatigue, decreased appetite
Decreased
appetite (2.5%), diarrhea (2.2%), QT prolongation (2.2%)
Dacomitinib
45
mg daily with or without food
Diarrhea, rash, paronychia, stomatitis, decreased appetite,
dry skin, decreased weight, alopecia, cough, pruritus
Rash
(23%), d
iarrhea (8%), paronychia
(8%), stomatitis (4.4%), decreased appetite (3.1%), decreased weight (2.2%), asthenia (2.2%)
20
Slide credit:
practicingclinicians.com
:
Slide21CHRYSALIS Study of
Amivantamab: Best ORR by Ex20ins Region
*1 patient discontinued prior to disease assessment and is not included in this analysis.
CBR = clinical benefit rate;
ctDNA
= circulating tumor DNA; ORR = overall response rate.
Park. J Clin Oncol. 2021;39:3391.
25 different ex20ins variants identified by NGS of ctDNA from 63 evaluable patient samples
Change From Baseline in Sum of
Target Lesion Diameter (%)
n = 80*
80
60
40
20
0
-20
-40
-60
-80
-100
Helical Region (n = 1)
ORR: 100%; CBR: 100%
Near Loop (n = 54)
ORR: 41%; CBR: 70%
Far Loop (n = 8)
ORR: 25%; CBR: 75%
Not Detected by ctDNA (n = 18)
ORR: 39%; CBR: 83%
Helical region (762-766)
Near loop region (767-772)
Far loop region (773-775)
Not detected by ctDNA
Ex20ins Location:
21
Slide credit:
practicingclinicians.com
:
Slide22IRRs primarily occurred during
first infusion (93% of cases); did not affect the ability to receive subsequent treatmentsIRR management strategies:Premedicate with glucocorticoid on Wk 1, Day 1 and Day 2Premedicate with acetaminophen and diphenhydramine with all dosesSplit the dose of the first infusion over 2 days (Day 1 and Day 2)If IRR is suspected, interrupt the drug and give supportive medications as neededAmivantamab: AEs
AE = adverse event; ALT = alanine aminotransferase; IRR = infusion-related reaction.
Park. J Clin Oncol. 2021;39:3391.
AEs in ≥15% of Patients, n (%)
Safety Population (N = 114)
All Grades
Grade ≥3
EGFR-related
Rash*
Paronychia
Stomatitis
Pruritus
98 (86)
51 (45)
24 (21)
19 (17)
4 (4)
1 (1)
0
0
MET-related
Hypoalbuminemia
Peripheral edema
31 (27)
21 (18)
3 (3)
0
Other
IRR
Constipation
Nausea
Dyspnea
Fatigue
ALT elevation
75 (66)
27 (24)
22 (19)
22 (19)
21 (18)
17 (15)
3 (3)
0
0
2 (2)
2 (2)
1 (1)
22
*Includes all rash-related AEs. Safety data cutoff: June 8, 2020.
Slide credit:
practicingclinicians.com
:
Slide23Data cutoff: November 1, 2020.
*DCR: confirmed CR or PR
or
best response of SD for ≥6 weeks from initiation of study drug.
CR = complete response; DCR = disease control rate;
DoR
= duration of response; NE = not evaluable; PR = partial response; SD = stable disease.
Zhou. JAMA Oncol. 2021;7:e214761.
Response
PPP Cohort
(n = 114)
EXCLAIM Cohort
(n = 96)
Confirmed ORR, % (95% CI)
CR
PR
28 (20-37)
0
28
25 (17-35)
0
25
Median DoR, mo (95% CI)
17.5 (7.4-20.3)
NE (5.6-NE)
Confirmed DCR,* % (95% CI)
78 (69-85)
76 (66-84)
Confirmed ORR, % (95% CI)
CR
PR
35 (26-45)
<1
34
32 (23-43)
1
31
Median DoR, mo (95% CI)
11.2 (5.6-NE)
11.2 (7.0-NE)
Confirmed DCR,* % (95% CI)
78 (69-85)
75 (65-83)
Independent Review Committee Assessments
Investigator Assessments
Antitumor Activity of Mobocertinib in Previously Treated
EGFR
ex20ins-Positive Metastatic NSCLC
23
Slide credit:
practicingclinicians.com
:
Slide24Safety profile consistent with other approved EGFR TKIs
TRAEs With Mobocertinib in ≥20% of PatientsPPP Cohort (n = 114)
EXCLAIM Cohort (n = 96)
Data cutoff: November 1, 2020.
PPP = platinum-pretreated patient; TRAE = treatment-related adverse event.
Zhou. JAMA Oncol. 2021;7:e214761.
Patients (%)
Patients (%)
24
Slide credit:
practicingclinicians.com
:
Slide25Varying Rates of High TMB (>10 mut/Mb)
68% G13 any have high TMB (median 11)58% G12C have high TMB (median 11)
43% G12D have low TMB (median 9)
Varying Rates of High PD-L1 TPS (>50%)
41% G12C have high PD-L1
35% G12D have high PD-L1
Comutations differ among
KRAS
mutations
The clinical relevance of differences in
KRAS
mutations subtype is unknown and should be further investigated
Characterization of
KRAS
Mutations in NSCLC
TMB = tumor mutational burden; TPS = tumor proportion score; WT = wild type
Liu. ASCO 2020. Abstr 9544.
Comutations by
KRAS
Subtype
WT
G12V
G12A
G12C
G13 any
Q61 any
G12D
G12 other
80
60
40
70
50
20
0
30
10
NGS-TP53
NGS-EGFR
NGS-CDKN2A
NGS-STK11
NGS-PTEN
NGS-BRAF
NGS-NFE2L2
NGS-KEAP1
NGS-ATM
NGS-ERBB2
NGS-U2AF1
NGS-NF1
NGS-GNAS
Percent
40%
G12C
19%
G12V
15%
G12D
G13 Any
G61 Any
G12A
KRAS
Mutation Subtypes in NSCLC
7%
7%
6%
4%
Other, 2%
G12 Other
25
Slide credit:
practicingclinicians.com
:
Slide26Phase II trial evaluating sotorasib 960 mg PO daily in patients with
KRAS G12C mutation-positive NSCLC who progressed on 1-3 prior standard therapies81% with both prior platinum-based chemotherapy and immunotherapyCodeBreaK100: Sotorasib in Pretreated Advanced KRAS G12C Mutation–Positive NSCLC
Dy.
AACR 2022. CT008.
*Assessed by central review.
Outcome
Sotorasib
960 mg Daily
(N = 174)
Confirmed ORR, % (95% CI)*
40.7 (33.2-48.4)
DCR, % (95% CI)
80.6 (72.6-87.2)
Median DoR,
mo
(95% CI)
12.3 (7.1-14.6)
Median PFS,
mo
(95% CI)
6.3 (5.3-8.2)
26
Number of Patients:
Event-Free Probability
Study Months
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
34
36
174
163
141
121
101
88
77
71
65
59
52
46
32
22
6
4
2
1
0
1
Yr
OS:
50.8% (42.8-58.2)
2
Yr
OS:
32.5% (25.0-40.2)
12.5 Mo:
(10.0-17.8)
Median OS (95% Cl)
Median follow-up: 24.9 months
Slide credit:
practicingclinicians.com
:
Slide27In May 2021, the FDA granted sotorasib accelerated approval for treatment of adult patients with locally advanced or metastatic
KRAS G12C-mutated NSCLC who received ≥1 prior systemic treatment27CodeBreaK100: Sotorasib TRAEs
Skoulidis, ASCO 21
TRAE, n (%)
Sotorasib 960 mg Daily (N = 126)
TRAE, n (%)
Any Grade
Grade 3
Any
88 (69.8)
25 (19.8)
Diarrhea
40 (31.7)
5 (4.0)
Nausea
24 (19.0)
0
ALT elevation
19 (15.1)
8 (6.3)
AST elevation
19 (15.1)
7 (5.6)
Fatigue
14 (11.1)
0
Vomiting
10 (7.9)
0
Blood ALP elevation
9 (7.1)
1 (0.8)
Maculopapular rash
7 (5.6)
0
ALP = alkaline phosphatase; AST = aspartate aminotransferase.
Skoulidis
. ASCO 2021. Abstr 9003. Skoulidis. NEJM. 2021; [
Epub
]. Sotorasib PI.
n = 1 (0.8%) with grade 4 TRAEs (pneumonitis and dyspnea).
Slide credit:
practicingclinicians.com
:
Slide28Found in ~5% of patients with NSCLC
Occurs more frequently in younger patients, light- or never-smokers
Predominantly a fusion of
ALK
with partner oncogenes, particularly
EML4
Occurs in similar subgroups as patients with
EGFR
mutations, but
EGFR
mutations and
ALK
rearrangements are typically mutually exclusive
ALK
Rearrangements
Shaw. J Clin Oncol. 2009;27:4247. Soda. Nature. 2007;448:561.
28
Slide credit:
practicingclinicians.com
:
Slide29*
P <.001. †P <.0001.Alectinib PI. Brigatinib PI. Camidge. J Thorac Oncol. 2021;16:2091. Ceritinib PI. Crizotinib PI. Lorlatinib PI. Mok. Ann Oncol. 2020;31:1056. Sholl. Transl Lung Cancer Res. 2017;6:560. www.nccn.org. Biomarker-Directed Therapy: ALK Rearrangements
Drug
Median PFS: First
L
ine (Comparator)
FDA
Indication(s)
Crizotinib
10.9
mo
* vs 7.0
mo
(CT)
Median
OS:
HR = 0.76, 95% CI: 0.55-1.05;
P
= NS
ALK
- or
ROS1
-positive
mNSCLC
Ceritinib
16.6
mo
†
vs 8.1
mo
(CT)
ALK
-positive
mNSCLC
Alectinib34.8 mo
† vs 10.9 mo
(crizotinib)Median OS: HR = 0.67, 95% CI: 0.46-0.98; P
= 0.037ALK-positive
mNSCLC Brigatinib
24.0 mo† vs 11.1 mo (crizotinib)PFS: HR = 0.48, 95% CI: 0.35-0.66
ALK-positive
mNSCLC
Lorlatinib
Not estimable
†
vs 9.3
mo
(crizotinib)
PFS: HR = 0.28, 95% CI: 0.19-0.41
ALK
-positive
mNSCLC in 1
st
line setting
2nd
line
after fr
ont-line
alectinib
or
ceritinib
Later line after crizotinib + ≥1 other
ALK inhibitor
29
Slide credit:
practicingclinicians.com
:
Slide30*Requires three 150-mg capsules or tablets.
†Requires four 200-mg capsules.URI = upper respiratory infection.Alectinib PI. Brigatinib PI.
Ceritinib PI. Crizotinib PI.
Lorlatinib
PI.
Mok
.
Ann Oncol. 2020;31:1056.
Sholl
.
Transl
Lung Cancer Res. 2017;6:560.
ALK Inhibitors: Dosing and Side Effects
Drug
Dosage
and
Administration
Frequent Side
Effect
s
Grade ≥3 Side Effects (≥2%)
Crizotinib
250 mg twice daily
Dose adjust for renal impairment
≥25%: Vision disorders, nausea,
diarrhea, vomiting, edema, constipation, elevated transaminases, fatigue, decreased appetite, URI, dizziness, neuropathy
QT prolongation (2%), diarrhea (2%), vomiting
(2%), constipation (2%), esophagitis (2%)
Ceritinib
450 mg* once daily
with food
≥25%: Diarrhea, nausea, abdominal pain, vomiting, fatigue
Fatigue
(7%), vomiting (5%), diarrhea (4.8%),
stomach pain (3.7%), weight loss (3.7%), nausea (2.6%), QT prolongation (2.6%)
Alectinib
600 mg
†
twice daily with food
≥20%: Fatigue, constipation, edema, myalgia, anemiaRenal impairment (3.9%), including 2 grade 5
Brigatinib
90 mg once daily x 7 days, then 180 mg once daily with or without food
≥25%: Diarrhea, fatigue, nausea, rash, cough, myalgia, headache, hypertension, vomiting, dyspnea
Hypertension (13%), pneumonia (5.1%), rash (2.9%), dyspnea (2.9%), pneumonitis (2.9%), diarrhea (2.2%), nausea (2.2%), pulmonary embolism (2.2%),
headache (2.2%)
Lorlatinib
100 mg once
daily
≥20%: Edema,
peripheral neuropathy, cognitive effects, dyspnea, fatigue, weight gain, arthralgia, mood effects, diarrhea
Dyspnea (5.7%), weight gain (4.4%),
edema (3.1%), peripheral neuropathy (2.7%), cognitive effects (2.0%)
30
Slide credit:
practicingclinicians.com
:
Slide31Most common in younger patients, never-smokers, adenocarcinoma, high-grade histology
Frequency: 1.2% to 1.7% overallBiomarker-Directed Therapy: ROS1 Fusions
Bergethon
. J Clin Oncol. 2012;30:863.
Crizotinib PI.
Davies. Clin Cancer Res. 2012;18:4570.
Dziadziuszko
. J Clin Oncol. 2021;39:1253. Entrectinib PI.
Shaw. Ann Oncol. 2019;30:1121.
Drug
Efficacy in First
L
ine
FDA
Indication(s)
Crizotinib
ORR: 72%
Median
DoR
:
24.7
mo
Median OS: 51.4
mo
ROS1
- or
ALK
-positive
mNSCLC
Entrectinib
ORR: 67.1%
DoR
of 15.7
mo
12-mo OS rate: 81%
Intracranial ORR: 79.2%
ROS1
-positive
mNSCLC
NTRK-
positive solid tumors
31
Slide credit:
practicingclinicians.com
:
Slide32Crizotinib PI. Entrectinib PI.
ROS1 Inhibitors: Dosing and Side EffectsDrug
Dosage
and
Administration
Frequent Side
Effect
s
Grade ≥3 Side Effects (≥2%)
Crizotinib
250 mg twice daily
Dose adjust for renal impairment
≥25%: Vision disorders, nausea,
diarrhea, vomiting, edema, constipation, elevated transaminases, fatigue, decreased appetite, URI, dizziness, neuropathy
QT prolongation (2%),
diarrhea (2%), vomiting
(2%), constipation (2%), esophagitis (2%)
Entrectinib
600 mg once daily
≥20%:
Fatigue, constipation, dysgeusia, edema, dizziness, diarrhea, nausea, dysesthesia, dyspnea, myalgia, cognitive impairment, weight gain, cough, vomiting, pyrexia, arthralgia, vision disorder
Dyspnea (6%), lung infections (6%), fatigue (5%), cognitive impairment (4.5%), hypotension
(2.8%),
urinary tract
infection (2.3%)
32
Slide credit:
practicingclinicians.com
:
Slide33Occurs predominantly in adenocarcinoma,
both patients with a history of smoking and never-smokersFrequency: 1% to 2% overallDabrafenib + trametinib approved for BRAF V600E-positive metastatic NSCLCIn previously untreated patients, ORR: 64%, median PFS: 10.9 months
In previously treated patients, ORR: 63.2%, median PFS: 9.7 monthsAny grade AEs, pyrexia (46%), nausea (40%), vomiting (35%), and diarrhea (33%);
most frequent grade ≥3 AE, neutropenia (9%)
Biomarker-Directed Therapy:
BRAF
V600E
Mutation
Chen. PLoS One. 2014;9:e101354.
Dabrafenib
PI. Paik. J Clin Oncol. 2011;29:2046.
Planchard
. Lancet Oncol. 2016;17:984.
Planchard
. Lancet
Oncol
. 2017;18:1307.
33
Slide credit:
practicingclinicians.com
:
Slide3440
20
0
-20
-40
-60
-80
-100
100
80
60
FDA approvals for
metastatic
MET
ex14+ NSCLC
Capmatinib: May 2020
Tepotinib: February 2021
Capmatinib and Tepotinib: 2 Approved Selective
MET Inhibitors for
MET
ex14-Positive Advanced NSCLC
Response
Prior Tx
Tx Naive
Capmatinib
(n = 100)
(n = 60)
ORR, %
44.0
66.7
Median DoR, mo
9.7
12.6
Median PFS, mo
5.5
12.3
Tepotinib
(n = 83)
(n = 69)
ORR, %
44.6
44.9
Median DoR, mo
11.1
10.8
Median PFS, mo
10.9
8.5
BOR = best overall response; IRC = independent review committee; PD = progressive disease.
Capmatinib
PI. Le. Clin Cancer Res. 2022;28:1117. Paik. NEJM. 2020;383:931. Tepotinib PI. Wolf. ASCO 2021.
Abstr
9020. Wolf. ELCC 2022.
Abstr
26P.
-100
-80
-60
-40
-20
Best % Change in Sum of
Target Lesion Diameters
Phase II GEOMETRY Mono-1: Best Tumor Response With Capmatinib in Tx-Naive
MET
ex14+ Adv NSCLC (n = 57)
Phase II VISION: Best Tumor Response With Tepotinib in
Tx-Naive
MET
ex14+ Adv NSCLC (n = 69)
Best % Change From Baseline (%)
*Patients still on treatment.
PR
SD
CR
*
*
*
*
*
*
*
*
*
*
*
0
20
BOR (IRC)
CR
PR
SD
PD
NE
34
Slide credit:
practicingclinicians.com
:
Slide35*R
equires two 200-mg tablets at each dose. †Requires two 225-mg tablets at each dose.Capmatinib PI. Tepotinib PI.Selective MET Inhibitors: Dosing and Side Effects
Drug
Dosage
and
Administration
Frequent Side
Effect
s (≥20%)
Grade ≥3 Side Effects (≥2%)
Capmatinib
400 mg twice daily
*
with or without
food
Peripheral edema, nausea, fatigue, vomiting, dyspnea, decreased appetite
Peripheral edema (9%), fatigue (8%), noncardiac chest pain (2.1%), nausea (2.7%), vomiting (2.4%), dyspnea (7%)
Tepotinib
450 mg once daily
†
with food
Edema, fatigue, nausea, diarrhea, musculoskeletal pain, dyspnea
Edema (9%), pleural effusion (5%), pneumonia (3.9%), musculoskeletal pain (2.4%), dyspnea (2%)
35
Slide credit:
practicingclinicians.com
:
Slide36Elevation
Compression stockings or sleevesPhysical therapy referralDiuretics – but not always effective; need to watch blood pressureOften not able to manage and may require dose reductions depending on patient’s quality of lifeManaging Edema Associated With Selective MET Inhibitor Therapy
36
Slide credit:
practicingclinicians.com
:
Slide37-20
-40
-60
-80
-100
20
Selpercatinib and Pralsetinib: 2 Approved Selective
RET Inhibitors for
RET
Fusion–Positive Advanced NSCLC
Response
Prior Plt-Based CT
Tx Naive
Selpercatinib
(n = 247)
(n = 69)
ORR, %
61.1
84.1
Median DoR, mo
28.6
20.2
Median PFS, mo
24.9
22.0
Pralsetinib
(n = 87)
(n = 27)
ORR, %
61
70
Median DoR, mo
NR
9.0
Median PFS, mo
17.1
9.1
Phase I/II ARROW: Best Tumor Response With
Pralsetinib in Tx-Naive
RET
+ Adv NSCLC (n = 68)
NR = not reached.
Besse
. ASCO 2021. Abstr 9065. Drilon. ELCC 2022.
Abstr
27P.
Gainor
. Lancet Oncol. 2021;22:959.
Selpercatinib
PI.
Pralsetinib
PI.
FDA approvals for metastatic
RET
+ NSCLC
Selpercatinib: May 2020
Pralsetinib: September 2020
Maximum Change From Baseline in Target Lesions Diameter (%)
Phase I/II LIBRETTO-001: Best Tumor Response With
Selpercatinib in Tx-Naive
RET
+ Adv NSCLC (n = 48)
% Change From Baseline by IRC
40
20
0
-20
-40
-60
-80
-100
0
100
Patients
KIF5B
CCDC6
Other
37
Slide credit:
practicingclinicians.com
:
Slide38*
Requires multiple 40- and/or 80-mg capsules at each dose. †Requires four 100-mg capsules. Pralsetinib PI. Selpercatinib PI.RET Inhibitors: Dosing and Side Effects
Drug
Dosage
and
Administration
Frequent Side
Effect
s (≥20%)
Grade ≥3 Side Effects (≥2%)
Selpercatinib
Weight-based:
<50 kg: 120 mg twice daily
*
≥50 kg: 160 mg twice daily
*
Dry mouth, diarrhea, hypertension, fatigue, constipation, nausea, abdominal pain, edema,
rash, headache
Hypertensio
n (18%), QT prolongation (4.0%), d
iarrhea (3.4%), dyspnea (2.3%)
Pralsetinib
400 mg once daily
†
Fatigue, constipation, musculoskeletal pain, hypertension
Decreased lymphocytes (20%)
and neutrophils (10%), h
ypertension (14%), pneumonia (8%), diarrhea (3%), fatigue (2.3%)
38
Slide credit:
practicingclinicians.com
:
Slide39*For
selpercatinib, may be able to increase to prior dose with close monitoring of AST/ALT.LFT = liver function test.Pralsetinib PI. Selpercatinib PI.Monitoring for and Managing Toxicity Associated With RET-Specific Inhibitors
AE
Monitoring
Dose Modifications
Hypertension
Optimize blood pressure before starting drug
Monitor blood pressure after 1 week, then monthly thereafter or as clinically indicated
Grade 3: Withhold if persists despite optimal antihypertensive therapy; resume at lower dose when controlled
Grade 4: Discontinue
Hepatotoxicity
Monitor AST/ALT prior to starting drug
,
every 2 weeks in first 3 months, then monthly thereafter or as clinically indicated
Grade 3/4: Withhold until resolution to grade 1 or baseline, with weekly LFTs; resume at reduced dose*
If recurs at grade ≥3, discontinue
Hemorrhagic events
Advise patients about risk of bleeding with drug and to contact their healthcare provider at any sign or symptom of bleeding
Grade 3/4: Withhold until recovery to grade 0 or 1 or to baseline
Discontinue for severe or life-threatening hemorrhagic events
39
Slide credit:
practicingclinicians.com
:
Slide40Gliomas
Infantile fibrosarcoma
Thyroid cancer
Congenital nephroma
Spitz nevi
Sarcoma (multiple)
Brain cancers (glioma, GBM, astrocytoma)
Thyroid cancer
Salivary (MASC)
Lung cancer (<1%)
Secretory breast cancer
Pancreatic
Cholangiocarcinoma
GIST
Colon
Melanoma
Sarcoma (multiple)
Normal role in neuronal development in utero and postnatal neuronal differentiation, survival, function; expression limited to CNS
NTRK
Rearrangements and
TRK
Fusions in Cancer
GBM = glioblastoma; GIST = gastrointestinal stromal tumor;
MASC = mammary analogue secretory carcinoma.
Cocco. Nat Rev Clin Oncol. 2018;15:731. Gatalica. AACR-NCI-EORTC 2017. Abstr A047. Hyman. ASCO 2017. Abstr LBA2501.
NTRK
Fusions Are Rare Events:
0.21% Across 11,116 Patients With Tumors of All Types
Common cancer with low
TRK fusion frequency
Rare cancer with high
TRK fusion frequency
40
Slide credit:
practicingclinicians.com
:
Slide4125
75
50
0
-25
-50
-75
-100
100
TRK Inhibitors Are Active in
TRK
Fusion–Positive Lung Cancer
Cho. ELCC 2022. Abstr 110P. Lin. ASCO 2021. Abstr 9109.
Larotrectinib
N = 15
ORR, % (95% CI)
73 (45-92)
Median DoR, mo
33.9
Median PFS, mo
35.4
Median OS, mo
40.7
Median follow-up, mo
16.2
Entrectinib
N = 22
ORR, % (95% CI)
63.6 (40.7-82.8)
Median DoR, mo*
19.9
Median PFS, mo
14.9
Median OS, mo
NE
Median follow-up, mo
19.2
Change in Tumor Size With
Entrectinib
(N =
20
)
*Among the 14 patients who responded
41
Change in Tumor Size With Larotrectinib (N = 15)
Best improvement From Baseline in SLD (%)
Individual Patients
Best confirmed overall response:
CR/PR (n=14) SD (n=3) PD (n=1) NE
†
(n=2)
*
*
*
*
*
*
*
*
*
*
*
*
25
50
0
-25
-50
-75
-100
Maximum Change in Tumor Size (%)
Patients
With CNS metastases
Without CNS metastases
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
†
Investigator-assessed as per RECIST v1.1. *Patients with investigator-assessed CNS metastases at baseline.
†
Patient with measurable intracranial disease and 100% reduction intracranial target lesions.
Slide credit:
practicingclinicians.com
:
Slide42*90% of HER2 mutations are in exon 20.
mOS
= median overall survival;
mPFS
= median progression-free survival.
Baraibar
. Crit Rev Oncol
Hematol
. 2020;148:102906. Li. JCO. 2018;36:2532.
Li. NEJM. 2022. 386:241.
For many patients diagnosed with advanced NSCLC, the best therapeutic option may be a clinical trial
If an emerging biomarker is identified, patient referral to a location with an appropriate study is encouraged
On the Horizon: Other Emerging Biomarkers for Treatment of Advanced NSCLC
Mutation
Incidence
Investigational Inhibitor(s)
Preliminary Efficacy
HER2
mutations, including ex20ins
2% to 4%*
Ado-trastuzumab emtansine
Trastuzumab
deruxtecan
ORR: 44%; mPFS: 5
mo
ORR: 55%; mPFS: 8.2 mo;
mOS
: 17.8 mo
42
Slide credit:
practicingclinicians.com
:
Slide43T-DXd:
HER2-targeted ADC coupling anti-HER2 mAb with same AA sequence as trastuzumab to topoisomerase I inhibitor payload using a tumor-selectable cleavable linkerPhase II Study: Trastuzumab Deruxtecan (T-DXd) in Pretreated HER2-Mutated Metastatic NSCLCAdjudicated drug-related ILD: n = 24 (26%); Gr 1, n = 3; Gr 2, n = 15; Gr 3, n = 4; Gr 5, n = 2
Median time to onset: 141 d (range: 14-462); median duration: 43 d
21/24 patients received glucocorticoids;
13/24 resolved at data cutoff
Li. NEJM. 2022;386:241.
Efficacy Outcome
Patients
(N = 91)
Confirmed ORR by ICR, n (%)
50 (55)
DCR, % (95% CI)
92 (85-97)
Median DoR, mo (95%)
9.3 (5.7-14.7)
Median PFS, mo (95%)
8.2 (6.0-11.9)
Drug-Related AEs in ≥20% of Patients,* %
Patients (N = 91)
Gr 1/2
Gr 3
Gr 4
All
Nausea
64
9
0
73
Vomiting
36
3
0
40
Neutropenia
16
15
3
35
Anemia
23
10
0
33
Diarrhea
29
2
1
32
Decreased appetite
30
0
0
30
Leukopenia
19
4
0
23
Constipation
22
0
0
22
*Not shown: any-grade fatigue (53%) and alopecia (46%).
43
Best % Change in Sum of Largest Tumor Diameters (n = 85)
0
40
20
-20
-40
-60
-80
-100
Change From Baseline (%)
Location of
HER2
Mutation:
Kinase domain Extracellular domain
Slide credit:
practicingclinicians.com
:
Slide44Choose therapy directed toward each patient’s specific NSCLC genotype
Most TKIs are now recommended as first-line therapy for patients with the specific targeted mutationFor many patients diagnosed with advanced NSCLC, the best therapeutic option may be a clinical trialPatients’ Specific Molecular Profile Determines Treatment Course44Slide credit: practicingclinicians.com
:
Slide45Choose therapy directed toward each patient’s specific NSCLC genotype
Most TKIs are now recommended as first-line therapy for patients with the specific targeted mutationFor many patients diagnosed with advanced NSCLC, the best therapeutic option may be a clinical trialPatients’ Specific Molecular Profile Determines Treatment Course
ACTION ITEM:
Select therapy based on the results of molecular profiling and the evidence from clinical trials
45
Slide credit:
practicingclinicians.com
:
Slide46Mo
0
2
4
6
8
10
12
0
20
10
-10
-20
-30
-40
-50
Phase II study of pembrolizumab in patients with PD-L1–positive
EGFR
-mutated advanced NSCLC (planned N = 25); stopped for futility at 11 patients
Lack of Efficacy With Immune Checkpoint Inhibition
in
EGFR
Mutation-Positive NSCLC
Lisberg
. J
Thorac
Oncol. 2018;13:1138.
Best Response for Target Lesions
Subsequent Therapies and Reasons
for Treatment Discontinuation
*AE led to discontinuation.
†
Completed treatment, under surveillance.
‡
Died while on erlotinib
(1 by fatal pneumonitis).
§
Report of
EGFR
mutation was in error.
EGFR-wild-type
§
Change From Baseline (%)
*
†
*
*
*
‡
‡
†
Pembrolizumab
No therapy
Erlotinib
Afatinib
Chemotherapy
Clinical trial
PD
Treatment ongoing
*Patient with dural thickening on brain MRI deemed to have PD.
†
Patient had CR of target lesion but nontarget progression on first scan.
‡
Report of
EGFR
mutation was in error.
EGFR-wild-type
‡
46
Slide credit:
practicingclinicians.com
:
Slide47Retrospective review of patient records to identify severe toxicity with ICI and EGFR TKI, regardless of sequence, in patients with
EGFR-mutated NSCLC (N = 126)In patients treated with osimertinib within 3 months of ICI, 24% developed a severe irAE; conversely, no severe irAEs were identified if osimertinib was given before ICIPotential Toxicity With Sequential Use of Immunotherapy Followed by a TKI
*Carboplatin + pemetrexed.
ICI = immune checkpoint inhibitor;
irAE
= immune-related adverse event;
Osi
= osimertinib.
Schoenfeld. Ann Oncol. 2019;30:839.
Pt No.
ICI
Days on ICI
Days Between ICI and Osi
Days to irAE Onset
After 1st Osi Dose
irAE
Hospitalized?
Response to Steroids?
1
Nivolumab
14
29
24
Grade 3 pneumonitis
Y
Y
2
Pembrolizumab + CT*
21
23
15
Grade 3 pneumonitis
N
Y
3
Nivolumab + ipilimumab
392
22
167
Grade 3 pneumonitis
Y
Y
4
Pembrolizumab
126
28
14
Grade 3 colitis
Y
N
5
Pembrolizumab
126
314
15
Grade 3 pneumonitis
Y
Y
6
Nivolumab
68
39
39
Grade 4 hepatitis
Y
N
47
Slide credit:
practicingclinicians.com
:
Slide48Patients’ Specific Molecular Profile Determines Treatment Course
48High PD-L1 expression does not exclude the presence of a targeted mutationEfficacy to immunotherapy potentially reduced in patients with a driver mutationGiving immunotherapy upfront in a patient who has a driver mutation may increase the risk of AEs with targeted therapy later
Slide credit: practicingclinicians.com:
Slide49High PD-L1 expression does not exclude the presence of a targeted mutation
Efficacy to immunotherapy potentially reduced in patients with a driver mutationGiving immunotherapy upfront in a patient who has a driver mutation may increase the risk of AEs with targeted therapy laterPatients’ Specific Molecular Profile Determines Treatment Course
ACTION ITEM:
Review molecular testing results before initiating treatment in patients with advanced NSCLC, even when their PD-L1 IHC results show high expression
49
Slide credit:
practicingclinicians.com
:
Slide50Immune checkpoint inhibitor monotherapy: pembrolizumab,* atezolizumab, cemiplimab
Immune checkpoint inhibitor + chemotherapyPembrolizumab/carboplatin/pemetrexed (Nsq)Atezolizumab/carboplatin/paclitaxel/ bevacizumab (Nsq)Atezolizumab/carboplatin/nab-paclitaxel (Nsq)Pembrolizumab/carboplatin/taxane (Sq)Nivolumab/ipilimumab + 2 cycles of CT (Sq/Nsq)Immune checkpoint inhibitor combination: nivolumab/ipilimumab2022 Paradigm for Immunotherapy in Advanced NSCLC Without an Actionable Mutation
*Single-agent pembrolizumab also approved for ≥1% PD-L1 but not broadly recommended by experts. IC = immune cell; TC = tumor cell.
NCCN. Clinical practice guidelines in oncology: NSCLC. v.3.2022.
Advanced NSCLC w/o Actionable Mutation
PD-1/PD-L1i
PD-1/PD-L1i + Chemotherapy
PD-1i + CTLA-4i + Chemotherapy
PD-1i + CTLA-4i
PD-1/PD-L1i + Chemotherapy
PD-1i + CTLA-4i + Chemotherapy
PD-1i + CTLA-4i
PD-1/PD-L1i + Chemotherapy
PD-1i + CTLA-4i + Chemotherapy
PD-L1 1%-49%*
PD-L1 ≥50%
PD-L1 <1%
Current first-line treatment paradigm based on PD-L1 expression in TC and/or IC
50
Slide credit:
practicingclinicians.com
:
Slide51Randomized, open-label phase III trial (data cutoff for interim analysis: January 21, 2021)
Primary endpoint: hierarchical evaluation of investigator-assessed DFS in 3 populationsStage II-IIIA with PD-L1 TC ≥1% (by PD-L1 SP264 IHC assay) → all randomized stage II-IIIA → ITT population (stage IB-IIIA)Key secondary endpoints: OS (ITT); DFS in stage II-IIIA with PD-L1 TC ≥50 (by PD-L1 SP264 IHC assay); 3-yr and 5-yr DFS in all 3 populations; safetyIMpower010: Study Design
ITT = intention-to-treat.
Felip
. Lancet Oncol. 2021; 398:1344.
Patients with completely resected stage IB-IIIA NSCLC per UICC/AJCC v7 (includes stage IB tumors
≥4 cm); ECOG PS 0/1; tumor tissue for PD-L1 analysis required
(N = 1280)
Atezolizumab
1200 mg every 3wk
for 16 cycles
(n = 507)
BSC
(n =
498
)
Survival
follow-up
No crossover allowed
Stratification by sex, stage (IB vs II vs IIIA), histology, PD-L1 tumor expression per SP142 assay (TC2/3 and any IC vs TC0/1 and IC2/3 vs TC0/1 and IC0/1)
Adjuvant chemotherapy*
for 1-4 cycles
(n = 1269)
*Cisplatin + pemetrexed, gemcitabine, docetaxel, or vinorelbine.
51
Slide credit:
practicingclinicians.com
:
Slide52IMpower010: DFS in Stage II-IIIA NSCLC With
PD-L1 TC ≥1% (Primary Endpoint)
Felip. Lancet Oncol. 2021; 398:1344.
Atezolizumab
(n = 248)
BSC
(n = 228)
Median DFS, mo (95% CI)
NE (36.1-NE)
35.3 (29.0-NE)
Stratified HR:
0.66 (95% CI: 0.50-0.88;
P
= .0039)
(crossed significance boundary)
Median follow up:
32.8 mo (range:
27.6
-39.0)
PD-L1 expression by SP263 assay.
100
80
60
40
20
0
54
0
3
6
9
12
15
18
21
24
27
30
33
36
39
42
45
48
51
Mo
DFS (%)
+
Atezolizumab
BSC
Patients at
Risk, n
48.2%
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
+
++
+
++
+
+
+
+
+
+
+
+
+
+
+
74.6%
60.6%
61.0%
+
+
+
+
+
+
+
+
+
+
+
248
228
235
212
225
186
217
169
206
160
198
151
190
142
181
135
159
117
13497111807659543831212214127863433FDA approved in October 2021 for adjuvant treatment following resection + platinum-based chemo in patients with stage II-IIIA NSCLC w/PD-L1 expression ≥1% on tumor cells 52Slide credit: practicingclinicians.com:
Slide53Surgery-Related Parameter in All Randomized Patients
Nivolumab + CT
(n = 179)
CT
(n = 179)
Surgery received/cancelled, %
83.2/15.6
75.4/20.7
Median duration of surgery, min (IQR)
185 (133-260)*
213.5 (150-283)
†
Surgery approach, %
Thoracotomy
Minimally invasive
Minimally invasive → open
59.1
‡
29.5
‡
11.4
‡
63
§
21.5
§
15.6
§
Type of surgery, %
#
Lobectomy
Pneumonectomy
77.2
‡
16.8
‡
60.7
§
25.2
§
Complete resection (R0), %
83.2
77.8
Phase III CheckMate 816: Neoadjuvant Nivolumab + Platinum CT for Resectable Stage IB-IIIA NSCLC
BICR = blinded independent central review; EFS = event-free survival,
pCR
= pathological complete response; IQR = interquartile range.
Forde. N
Eng
J Med. 2022;epub ahead of print. Nivolumab PI.
pCR
(ITT; ypT0N0)
2.2
40
30
20
10
0
24.0
Difference: 21.6%
OR: 13.94
(99% CI: 3.49-55.75)
P
<.0001
CT
(4/179)
Nivo + CT
(43/179)
pCR Rate (%)
n/N =
*n = 122.
†
n = 121.
‡
n = 149.
§
n = 135.
#
Calculated from patients who received definitive surgery. Patients may have had ≥1 surgery type.
FDA
approved in March
2022 for adults with
resectable
NSCLC (tumors ≥4 cm or N+) in combination with platinum doublet CT in the neoadjuvant setting
Co-Primary Endpoints: EFS by BICR,
pCR
Median EFS 31.6 mo with
nivo
+ CT vs 20.8 mo; HR 0.63 (97.38% CI: 0.43-0.91);
P
= .005
53Slide credit: practicingclinicians.com:
Slide54Initial diagnosis
Stage IB-IIIA, resected: EGFRStage II-IIIA, resected: PD-L1Metastatic disease: comprehensive biomarker testing (NGS panel)Locally advanced, receiving definitive chemoradiationCurrently no indications for approvals, but consideration….Summary: When to Test?Disease progression
In EGFR, can be resistance mechanisms that are targetable (T790M, SCLC transformation, MET or HER2 resistance, clinical trials)
For other biomarkers, mostly informational for clinical trials
Disease recurrence
Try to retest, especially if has been a long interval from definitive therapy
54
Slide credit:
practicingclinicians.com
:
Slide55PCE Action Plan
Slide56Order biomarker testing, preferably NGS, to identify actionable mutations in all patients with advanced
nonsquamous NSCLC; consider in squamous NSCLC Select therapy based on the results of molecular profiling and the evidence from clinical trialsReview molecular testing results before initiating treatment in patients with advanced NSCLC, even when their PD-L1 IHC results show high expressionPCE Action Plan
PCE Promotes Practice Change
56
Slide credit:
practicingclinicians.com
:
Slide57