Interview with Shirish M Gadgeel MD January 14 2020 Case 1 72yearold woman enrolled on KEYNOTE021 2014 72yearold female patient with chest pain cough and dyspnea is diagnosed with Stage IV squamous cell carcinoma ID: 917382
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Slide1
iJOURNAL CLUB: Optimizing Therapy for Patients with Metastatic Squamous Cell Carcinoma of the Lung
Interview with Shirish M
Gadgeel
, MD
January 14, 2020
Slide2Case 1: 72-year-old woman enrolled on KEYNOTE-021
2014: 72-year-old female patient with chest pain, cough and dyspnea is diagnosed with Stage IV squamous cell carcinoma
Patient had lymph node and bone metastases
Enrolled on KEYNOTE-021 and received carboplatin, paclitaxel and pembrolizumab x 4 cycles followed by maintenance pembrolizumab
January 2016: Completed therapy; on surveillance
In 2014 it was not routine to assess tumor PD-L1
No recurrence of disease
Slide3Case 1: 72-year-old woman enrolled on KEYNOTE-021
February 2014
October 2014
Slide4The Evolving Use of Pembrolizumab in Combination Treatment Approaches for Non-Small Cell Lung Cancer
Alexander M
et al.
Expert Rev Respir Med
2020;14(2):137-47.
Slide5The Evolving Use of Pembrolizumab in Combination Treatment Approaches for NSCLC
Alexander M et al.
Expert Rev Respir
Med
2020;14(2):137-47.
Immune checkpoint inhibitors (ICI), particularly the anti-PD-1 inhibitor pembrolizumab (
pembro
), are now an established part of routine care for the majority of patients diagnosed with advanced NSCLC.
In the advanced setting, patients with PD-L1 TPS ≥50% benefit from
pembro
monotherapy, while a combination of
pembro
with chemotherapy is most beneficial for patients with PD-L1 TPS <50%.
Several studies have shown that consolidation ICI, including
pembro
, confers benefit for unresectable NSCLC after radiation therapy.
Validation of biomarkers other than PD-L1 TPS would be beneficial in identifying patients who would benefit from ICI to ensure a durable response, minimize immune-related adverse events and decrease treatment costs.
Slide6Combination Pembrolizumab plus Chemotherapy: A New Standard of Care for Patients with Advanced Non-Small-Cell Lung Cancer
Weinberg F
et al.
Lung Cancer (
Auckl
)
2019;10:47-56.
Slide7Front-Line Therapy for Advanced NSCLC
Weinberg F et al.
Lung Cancer (
Auckl
)
2019;10:47-56.
NSCLC
PD-L1 ≥50%
pembrolizumab
EGFR –
osimertinib
ALK –
alectinib
ROS1 –
crizotinib
BRAFV600E – dabrafenib + trametinib
PD-L1 ≥50%
pembrolizumab
(may consider chemo +
pembro
)
PD-L1 = 0%-49%
chemo +
pembro
PD-L1 = 0%-49%
chemo +
pembro
TMB may be assessed and if high
nivo
/
Ipi could be a consideration—CheckMate 227
Squamous
Marker-positive(EGFR, ALK, ROS1, BRAF)
Nonsquamous
Slide8Results with Chemotherapy and Immunotherapy Trials for Advanced NSCLC
Weinberg F et al.
Lung Cancer (
Auckl
)
2019;10:47-56.
Trial
Treatment arm
PFS (months)
HR (95% CI)
OS
(months)
HR (95% CI)
KEYNOTE-21G
Pembrolizumab/platinum/pemetrexed
13
0.53 (0.31-0.91)
ND
0.90 (0.81-0.96)
KEYNOTE-189
Pembrolizumab/platinum/pemetrexed
8.8
0.52 (0.43-0.64)
NR
0.49 (0.38-0.64)
IMpower132
Atezolizumab
/platinum/pemetrexed
7.6
0.60 (0.49-0.72)
18.1
0.81 (0.64-1.03)
IMpower150
Atezo
/Carbo/Pac
Atezo
/Bev/Pac/Carbo
8.30.62 (0.52-0.74)19.20.78 (0.64-0.74)
Summary of results from chemotherapy + immunotherapy trials for patients with advanced nonsquamous NSCLC
PFS = progression-free survival; OS = overall survival; ND = not determined; NR = not reached; Atezo = atezolizumab; Carbo = carboplatin; Pac = paclitaxel; Bev = Bevacizumab
TrialTreatment armPFS (months)HR (95% CI)OS (months)HR (95% CI)KEYNOTE-407Pembrolizumab/Carbo/PacNab-Pac6.40.56 (0.45-0.70)15.90.64 (0.49-0.85)IMpower131Atezo/Platinum/PacNab-Pac6.30.72 (0.66-0.85)140.96 (0.78-1.18)
Summary of results from chemotherapy + immunotherapy trials for patients with advanced squamous NSCLC
Slide9Hellmann MD
et al.
N
Engl
J Med
2019;381(21):2020-31.
Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer
Slide10Hellmann MD et al.
N
Engl
J Med
2019;3
81(21):2020-31.
CheckMate
227: Overall Survival with Nivolumab/Ipilimumab versus Chemotherapy
First-line treatment with nivolumab and ipilimumab resulted in a longer duration of overall survival than did chemotherapy for patients with NSCLC, independent of PD-L1 expression level.
No new safety concerns emerged with longer follow-up.
Median OS (
mo
)
P-
value
Nivo
+
Ipi
Chemotherapy
PD-L1 ≥1% (n = 396, 397)
17.1
mo
14.9
mo
0.007
PD-L1 <1% (n = 187, 186)
17.2
mo
12.2
mo
Not reported
Slide11Spigel
DR
et al.
Proc ESMO
2019;Abstract LBA78.
IMpower110: Interim Overall Survival (OS) Analysis of a Phase III Study of
Atezolizumab
(
Atezo
) vs Platinum-Based Chemotherapy (Chemo) as First-Line (1L) Treatment (
tx
) in PD-L1–Selected NSCLC
Slide12IMpower110: Interim Overall Survival Analysis of Atezolizumab versus Platinum-Based Chemotherapy
At this interim analysis, IMpower110 met the primary OS endpoint with statistically significant and clinically meaningful improvement
with
atezolizumab
monotherapy
in the TC3 or IC3 WT population.
Spigel
DR et al.
Proc ESMO
2019;
Abstract LBA78.
Atezolizumab
Chemotherapy
HR,
p-
value
n
Median OS (
mo
)
n
Median OS (
mo
)
TC3 or IC3 WT
107
20.2
98
13.1
0.59, 0.0106
TC2/3 or IC2/3 WT
166
18.2
162
14.9
0.72, 0.0416
TC1/2/3 or IC1/2/3 WT
277
17.527714.1
0.83, 0.1481
Slide13Cancer Site and Adverse Events Induced by Immune Checkpoint Inhibitors: A Retrospective Analysis of Real-Life Experience at a Single Institution
Sukari
A
et al.
Anticancer Res
2019;39(2):781-90.
Slide14Cancer Site and Adverse Events Induced by Immune Checkpoint Inhibitors
Retrospective analysis of 168 patients who received ≥1 dose of single-agent PD-1 inhibitor.
Patients with renal cell carcinoma had higher odds of experiencing Grade 2 or higher kidney injury than patients with other primary tumor types (adjusted
p
= 0.025).
Patients with Hodgkin lymphoma or head and neck squamous cell carcinoma had higher odds of Grade 2 hypothyroidism (adjusted
p
= 0.005). Patients with NSCLC had higher risk of death with pneumonitis than those whose primary cancer was not NSCLC (adjusted
p = 0.005).When pneumonitis occurred in patients with primary NSCLC, the overall survival was significantly worse. The site of primary tumor or metastasis may help predict the most common AEs in patients who receive PD-1 inhibitors.
Sukari
A et al.
Anticancer Res
2019;39(2):781-90.
Slide15Afatinib versus Erlotinib as Second-Line Treatment of Patients with Advanced Squamous Cell Carcinoma of the Lung (LUX-Lung 8): An Open-Label Randomised Controlled Phase III Trial
Soria JC et al
.
Lancet Oncol
2015;16(8):897-907.
Slide16Afatinib
(n = 398)
Erlotinib
(n = 397)
R
Phase III LUX-Lung 8 Trial Design
Primary endpoint:
Progression-free survival
Secondary endpoints included:
Overall survival, objective response rate
Eligibility (n = 795)
Stage IIIB or IV squamous cell carcinoma of the lung
Disease progression after at least four cycles of a first-line platinum-based regimen
Soria JC et al.
Lancet Oncol
2015;16(8):897-907.
1:1
Slide17LUX-Lung 8: Primary Analysis of PFS and OS
Primary Endpoint: PFS
Primary analysis of OS demonstrated significantly greater OS in the
afatinib
group than in the erlotinib group (median 7.9
mo
vs 6.8
mo
; HR 0.81,
p
= 0.0077).
Soria JC et al.
Lancet Oncol
2015;16(8):897-907.
Slide18LUX-Lung 8: Select Grade 3/4 Adverse Events
Adverse event profiles were similar in each group: 224 (57%) of 392 patients in the
afatinib
group versus 227 (57%) of 395 in the erlotinib group had grade 3 or higher adverse events.
Soria JC et al.
Lancet Oncol
2015;16(8):897-907.
AE
Afatinib
(n = 392)
Erlotinib (n = 395)
Grade 3
Grade 4
Grade 3
Grade 4
Diarrhea
10%
<1%
2%
<1%
Rash or acne
6%
0%
10%
0%
Stomatitis
4%
0%
0%
0%
Fatigue
2%
0%
2%
0%
Nausea
1%
0%
<1%
0%
Slide19Second-Line Afatinib for Advanced Squamous Cell Carcinoma of the Lung: Analysis of Afatinib Long-Term Responders in the Phase III LUX-Lung 8 Trial
1
LUX-Lung 8 Phase III Trial: Analysis of Long-Term Response to Second-Line
Afatinib
in Patients with Advanced Squamous Cell Carcinoma (SCC) of the Lung
2
1
Goss G et al.
Proc IASLC 2016;Abstract OA23.03.2
Yang JC-H et al.Proc ELCC 2017;Abstract 102P.
Slide20LUX-Lung 8: Post-hoc Analysis of Long-Term Responders (LTRs) with
Afatinib
Goss G et al.
Proc IASLC
2016;Abstract OA23.03; Yang JC-H et al.
Proc
ELCC
2017;Abstract 102P
.
N = 21 patients considered LTRs (
afatinib
treatment for ≥12 months).
Baseline characteristics of LTRs to
afatinib
were similar to that of the overall data set.
NGS data available for 10 LTRs and genomic aberrations in the ErbB gene family were identified in 50% of these pts (overall data set: 26.5%).
Other genomic aberrations more frequent in LTRs: EGFR, MLL, PIK3CA and KEAP1
Of 17 pts assessed by VeriStrat, 88% were VeriStrat-Good (overall data set: 62%).
Efficacy Endpoint
LTRs (N = 21)
Median PFS
16.6 months
Median OS
21.1 months
Slide21Association of ERBB Mutations with Clinical Outcomes of Afatinib- or Erlotinib-Treated Patients with Lung Squamous Cell Carcinoma: Secondary Analysis of the LUX-Lung 8 Randomized Clinical Trial
Goss GD et al
.
JAMA Oncol
2018;4(9):1189-97.
Slide22LUX-Lung 8: Secondary Analysis of ERBB Gene Family Mutations
Goss GD et al.
JAMA Oncol
2018;4(9):1189-97.
245 patients with PFS >2
mo
who were eligible for tumor genetic analysis (TGA)
Overall, the genetic characteristics of squamous cell carcinoma tumors in the TGA cohort were similar to those in the TCGA analysis
Frequency of ERBB Family Mutations in the Overall TGA Cohort and in
Patients Who Were LTRs to
Afatinib
Gene
TGA Subset (n = 245)
Afatinib
LTRs (n = 10)
ERBB wild type
78.4%
50.0%
ERBB mutation
EGFR
HER2
HER3
HER4
21.6%
6.5%
4.9%
6.1%
5.7%
50.0%
20.0%
20.0%
0%
10.0%
Slide23LUX-Lung 8: Secondary Analysis of PFS and ERBB Gene Family Mutations and PFS
Goss GD et al.
JAMA Oncol
2018;4(9):1189-97.
For patients receiving
afatinib
, PFS was longer among patients with tumors with ERBB mutations than those without (median PFS: 4.9 vs 3.0 months; HR 0.62;
p
= 0.06).
Slide24LUX-Lung 8: Secondary Analysis of PFS and ERBB Gene Family Mutations and OS
Goss GD et al.
JAMA Oncol
2018;4(9):1189-97.
For patients receiving
afatinib
, OS was longer among patients with tumors with ERBB mutations than those without (median OS: 10.6
mo
vs 8.1
mo
; HR, 0.75;
p
= 0.21).
Slide25LUX-Lung 8: Secondary Analysis of PFS and OS Among Patients with and without EGFR, HER2, HER3 and HER4 Mutations
Goss GD et al.
JAMA Oncol
2018;4(9):1189-97.
Slide26EDITORIAL: Association of ERBB Mutations with Clinical Outcomes of Afatinib- or Erlotinib-Treated Patients with Lung Squamous Cell Carcinoma: Secondary Analysis of the LUX-Lung 8 Randomized Clinical Trial
Gandara DR et al
.
JAMA Oncol
2018;4(9):1197-8.
Slide27Gandara DR et al.
JAMA Oncol
2018;4(9):1197-8.
“… no substantial progress has been made in the clinical application of targeted therapy for patients with squamous cancers … despite the discovery of a number of potential molecular targets and the initiation of associated clinical trials.”
“Thus, the study by Goss et al in this issue of JAMA Oncology identifying ERBB family mutations as potential oncogenic drivers in squamous lung cancer is timely.”
“For those squamous lung cancers found to harbor an oncogenic ERBB mutation, treatment with
afatinib
appears to be a reasonable option as second- or third-line therapy dependent on the initial treatment regimen.”
Slide28Activity of Afatinib in Heavily Pretreated Patients with ERBB2 Mutation-Positive Advanced NSCLC: Findings from a Global Named Patient Use Program
Peters S et al
.
J Thoracic Oncol
2018;13(12):1897-905.
Slide29Patients with any ERBB2 mutation
(n = 28)
Patients with
p.A775_G776insYVMA
in Exon 20 (n =10)
Patients with
M774dup in
Exon 20 (n = 2)
Median TTF
2.9
mo
9.6
mo
1.9
mo
ORR/PR
19.0%/19.0%
33.0%/33.0%
ND/ND
Efficacy of
Afatinib
and Types of ERBB2 Mutations Detected in Patients Enrolled in Global Named Patient Use Program*
Peters S et al.
J Thoracic Oncol
2018;13(12):1897-905.
*
Patients with Stage IV lung adenocarcinoma that progressed after clinical benefit on erlotinib/gefitinib and/or had activating EGFR or ERBB2 mutations, had exhausted other treatments and were ineligible for
afatinib
trials
10
162
Slide30Updated Results of Phase I Study of DS-8201a in HER2-Expressing or -Mutated Advanced Non-Small-Cell Lung Cancer
Tsurutani
J
et al.
Proc IASLC
2018;Abstract OA02.07.
Slide31Phase I Study of DS-8201a for Patients with NSCLC with HER2 Expression or Mutation
Patients (n = 12) with NSCLC with HER2 expression or mutations who had received a median of 3 prior regimens received ≥1 dose of DS-8201a.
Eight of 10 (80.0%) patients with ≥1 postbaseline scan experienced tumor shrinkage (100% of them at first postbaseline scan at 6 weeks).
Overall, confirmed ORR and DCR for the evaluable patients were 5 of 8 (62.5%) and 6 of 8 (75.0%), respectively.
Among patients with HER2 IHC 2+ or IHC 3+ expression, 2 of 5 (40.0%) had a PR.
Common AEs included decreased appetite 66.7% (0.0% Grade ≥3), nausea
58.3% (0.0% Grade ≥3), alopecia 41.7% (0.0% Grade ≥3) and fatigue 41.7%
(0.0% Grade ≥3).
One fatal case of interstitial lung disease was reported in this subgroup.
Tsurutani
J
et al.
Proc IASLC
2018;Abstract OA02.07
Slide32Ado-Trastuzumab Emtansine for Patients with HER2-Mutant Lung Cancers: Results from a Phase II Basket Trial
Li BT
et al.
J Clin Oncol
2018;36(24):2532-7.
Slide33Phase II Trial of T-DM1 for Lung Cancers with HER2 Mutation
Patients (n = 18) with advanced lung adenocarcinomas with HER2 mutations (median no. of prior therapies was 2) received T-DM1 until disease progression
Partial response rate: 44% (primary endpoint was met)
Responses were observed in patients with HER2 exon 20 insertions and point mutations in the kinase, transmembrane and extracellular domains
Median PFS: 5 months
Toxicities included Grade 1 and 2 infusion reactions, thrombocytopenia and elevated hepatic transaminases
Li BT et al.
J Clin Oncol
2018;36(24):2532-7
Slide34Afatinib in Patients with Metastatic or Recurrent HER2-Mutant Lung Cancers: A Retrospective International Multicentre Study
Lai WV et al
.
Eur J Cancer
2019;109:28-35.
Slide35Efficacy of
Afatinib
and Types of HER2 Mutations Detected in Patients Enrolled in Retrospective International Multicenter Study*
Lai WV et al.
Eur J Cancer
2019;109:28-35.
*
Eligible patients from 7 institutions who had a pathologic diagnosis of advanced (Stage IV or recurrent) lung adenocarcinoma and a HER2 mutation by a validated molecular diagnostic test that was performed in an accredited local laboratory
HER2 mutation
Mutation amino acid change
(nucleotide change)
Frequency
(%)
Partial
response
Progressive
disease
Exon 20 insertion (12bp)
p.A775_G776insYVMA (c.2324_2325ins12)
15 (54)
n = 2
n = 2
Exon 20 insertion (12bp)
p.A775_G776insAVMA
1 (4)
Exon 20 insertion (9bp)
p.A775_G776lnsVAG (c.2325_2326lns 9)
2 (7)
n = 1
Exon 20 insertion (9bp)
p.P780_Y781
insGSP
(c.2339_2340ins 9)
1 (4)
n = 1
Exon 20 insertion (3bp)
p.G776>VC (c.2326_2327insTGT)
1 (4)
Exon 20 insertion (3bp)
Not specified
1 (4)n = 1Exon 20 single bp substitutionP.D769H (C.2305 G>C)1 (4)n = 1Exon 20 single bp substitutionp.L755F1 (4)n = 1Exon 17 single bp substitutionP.V659E (c.1976_1977delinsAA)1 (4)n = 1Exon 8 single bp substitutionP.S310F (c.929C>T)2 (7)
Single-nucleotide polymorphism
lle655Val
1 (4)
Slide36Case 2: 82-year-old man diagnosed with Stage III squamous cell carcinoma of the lung develops liver metastases
An 82-year-old man diagnosed with Stage III squamous cell carcinoma of the lung
Receives chemoradiation therapy followed by
durvalumab
Develops liver metastases
NGS shows FGFR1 amplification (approximately 9 copies)
Receives carboplatin/paclitaxel, 4 cycles, with stable disease
Disease progression a few months laterPatient is considered for gemcitabine and afatinib. Decides to start gemcitabine but is very fatigued and opts to enroll in hospice
Slide37Comprehensive Genomic Characterization of Squamous Cell Lung Cancers
Cancer Genome Atlas Research Network.
Nature
2012;489(7417):519-25.
Slide38Significantly Mutated Genes in Squamous Cell Carcinoma (
SqCC
) of the Lung Identified by Whole Exome Sequencing
Cancer Genome Atlas Research Network.
Nature
2012;489(7417):519-25.
As part of The Cancer Genome Atlas, 178 samples of
SqCC
of the lung samples were profiled
Syn.
Non syn.
# mutations/Mb
70
50
30
10
# individuals with mutations
100
80
60
40
20
0
81%
15%
8%
16%
12%
20%3%15%8%7%Syn.MissenseSplice siteNonsenseFrame shiftIn frame indelOther non syn.TP53CDKN2APTENPIK3CAKEAP1MLL2HLA-ANFE2L2NOTCH1RB10.5
2.03.5-log (q-value)
Slide39Lung Master Protocol (Lung-MAP) — A Biomarker-Driven Protocol for Accelerating Development of Therapies for Squamous Cell Lung Cancer: SWOG S1400
Herbst RS et al.
Clin Cancer Res
2015;21(7):1514-24.
Slide40S1400: Lung-MAP Trial Design
Herbst RS et al.
Clin Cancer Res
2015;21(7):1514-24.
CT
CT = chemotherapy (
docetaxel
or gemcitabine)
;
E =
erlotinib
FGFRi
+ CT
CT
Primary Endpoint
OS
FGFR
ampl
,
Mut
, Fusion
CDK4/6i
CT
Primary Endpoint
OS
CCND1
ampl
or CDK4/6
ampl
or
CDKN2 loss + RB WT
PI3Ki
CT
Primary Endpoint
OS
PiK3CA
Mut
Biomarker
Profiling (NGS/CLIA)
HGFi
+ EEPrimary EndpointOSMET Expr(IHC score)PD-L1i BiomarkerNon-Match
Multiple Phase II-
III arms
with
“
rolling opening & closure”
Slide41SWOG S1400B (NCT02785913), a Phase II Study of GDC-0032 (Taselisib) for Previously Treated PI3K-Positive Patients with Stage IV Squamous Cell Lung Cancer (Lung-MAP Sub-Study)
Langer CJ et al.
J
Thorac
Oncol
2019;14(10):1839-46.
Slide42SWOG S1400C (NCT02154490) — A Phase II Study of Palbociclib for Previously Treated Cell Cycle Gene Alteration-Positive Patients with Stage IV Squamous Cell Lung Cancer (Lung-MAP Substudy)
Edelman MJ et al.
J
Thorac
Oncol
2019;14(10):1853-9.
Slide43SWOG S1400D (NCT02965378), a Phase II Study of the Fibroblast Growth Factor Receptor Inhibitor AZD4547 in Previously Treated Patients with Fibroblast Growth Factor Pathway-Activated Stage IV Squamous Cell Lung Cancer (Lung-MAP Substudy)
Aggarwal C et al.
J
Thorac
Oncol
2019;14(10):1847-52.
Slide44Updated Results of Completed Phase II Lung-MAP
Substudies
1
Langer CJ et al.
J
Thorac
Oncol
2019;14(10):1839-46;
2
Edelman MJ et al.
J
Thorac
Oncol
2019;14(10):1853-9;
3
Aggarwal C et al.
J
Thorac
Oncol
2019;14(10):1847-52.
Substudy
Evaluable Patients
Response:
Patients (%)
Median PFS
Median OS
SWOG S1400B
1
(NCT02785913)Taselisib: 21
1 (5%)2.9 mo
5.9 moSWOG S1400C2(NCT02154490)
Palbociclib: 322 (6%)
1.7 mo7.1 mo
SWOG S1400D3(NCT02965378)
AZD4547: 272 (7%)
2.7
mo
7.5
mo
Slide45Case 3: 52-year-old woman with metastatic NSCLC with an ALK rearrangement experiences a dramatic response to crizotinib
A 52-year-old woman diagnosed in 2010 with metastatic lung adenocarcinoma and spinal cord compression was admitted to hospice care at home in December 2010
She checked out of hospice to enroll in the PROFILE 1014 study randomly assigning patients with NSCLC with ALK rearrangements to
crizotinib
versus chemotherapy
She was randomly assigned to chemotherapy and attained stable disease
She crossed over to the
crizotinib
arm in February 2012 and experienced a dramatic response The patient developed disease progression in the brain in June 2014 and was switched to
ceritinib but did not tolerate itShe was switched to alectinib with a CR in the brain and is currently on therapy with this drug