This document provides an overview of evolving understanding of biomarkers for response to immune checkpoint inhibition in non-small cell lung cancer (NSCLC). Key points include:
1) Clinical benefit of immunotherapy is seen across all levels of PD-L1 expression, including in patients with <1% PD-L1 expression, though benefit increases with higher PD-L1 levels.
2) Tumor mutational burden (TMB) and PD-L1 expression identify distinct patient populations.
3) PD-L1 testing has limitations due to intratumoral heterogeneity and potential sampling errors from small biopsies.
4) Several studies demonstrate superior outcomes for first-line pembrolizumab or ate
4-yr OS after 2nd-line Nivolumab, pooled analysis (based on Scott Antonia pre...Mauricio Lema
This document discusses long-term survival outcomes with nivolumab treatment in patients with previously treated advanced non-small cell lung cancer. It finds that early disease control, defined as stable or shrinking tumors after 3 months of treatment, as well as achieving an objective response, are associated with improved long-term survival. Patients who achieved early disease control had a median overall survival of 49.2 months compared to 11.3 months for those without early disease control. Similarly, patients who achieved an objective response had a median overall survival of not reached compared to 11.4 months for non-responders. The study demonstrates that nivolumab provides long-term survival benefits in this patient population.
Integración de la inmunoterapia en NSCLCMauricio Lema
This document discusses immunotherapy integration for NSCLC in the second line setting. It summarizes:
1) Key mechanisms of tumor immunology including PD-1/PD-L1 interactions and how they can be targeted by drugs like pembrolizumab.
2) Outcomes from first-line chemotherapy for NSCLC, noting median OS of 10-12 months and ORR of 30%.
3) Results from KEYNOTE-024 showing superior PFS and OS for pembrolizumab compared to chemotherapy as first-line treatment in patients with PD-L1 expression ≥50%.
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This document summarizes information on angiogenesis and lung cancer treatment. It discusses the types of lung carcinomas and relevant molecular drivers. It then presents a case study of a patient diagnosed with stage IV lung adenocarcinoma and discusses potential first-line and maintenance treatment options. The document contrasts treatment approaches with and without the use of anti-angiogenic drugs such as bevacizumab, noting their potential benefits but also risks of side effects.
1) Non-small cell lung cancer (NSCLC) accounts for 85-90% of lung cancers, with 10-15% being small cell lung cancer (SCLC). NSCLC can be divided into squamous cell carcinoma and non-squamous cell carcinoma.
2) Approximately 25-40% of patients with NSCLC present with locally advanced (Stage III) disease which has a low 5-year survival rate. Around 30% present with unresectable Stage III disease.
3) The KEYNOTE-189 trial showed that pembrolizumab plus chemotherapy improved overall survival compared to placebo plus chemotherapy as first-line treatment for Stage IV non-squamous NSCLC, regardless of PD-L1 expression
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The document discusses lung cancer subtypes and molecular features that can guide treatment. It provides statistics on the distribution of histology types among lung cancer cases. It also summarizes several key studies investigating targeted therapies such as EGFR TKIs versus chemotherapy as first-line treatment for advanced non-small cell lung cancer, noting improved progression-free survival with TKIs in patients with EGFR mutations. Molecular testing is increasingly important for determining personalized treatment approaches in lung cancer.
4-yr OS after 2nd-line Nivolumab, pooled analysis (based on Scott Antonia pre...Mauricio Lema
This document discusses long-term survival outcomes with nivolumab treatment in patients with previously treated advanced non-small cell lung cancer. It finds that early disease control, defined as stable or shrinking tumors after 3 months of treatment, as well as achieving an objective response, are associated with improved long-term survival. Patients who achieved early disease control had a median overall survival of 49.2 months compared to 11.3 months for those without early disease control. Similarly, patients who achieved an objective response had a median overall survival of not reached compared to 11.4 months for non-responders. The study demonstrates that nivolumab provides long-term survival benefits in this patient population.
Integración de la inmunoterapia en NSCLCMauricio Lema
This document discusses immunotherapy integration for NSCLC in the second line setting. It summarizes:
1) Key mechanisms of tumor immunology including PD-1/PD-L1 interactions and how they can be targeted by drugs like pembrolizumab.
2) Outcomes from first-line chemotherapy for NSCLC, noting median OS of 10-12 months and ORR of 30%.
3) Results from KEYNOTE-024 showing superior PFS and OS for pembrolizumab compared to chemotherapy as first-line treatment in patients with PD-L1 expression ≥50%.
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This document summarizes information on angiogenesis and lung cancer treatment. It discusses the types of lung carcinomas and relevant molecular drivers. It then presents a case study of a patient diagnosed with stage IV lung adenocarcinoma and discusses potential first-line and maintenance treatment options. The document contrasts treatment approaches with and without the use of anti-angiogenic drugs such as bevacizumab, noting their potential benefits but also risks of side effects.
1) Non-small cell lung cancer (NSCLC) accounts for 85-90% of lung cancers, with 10-15% being small cell lung cancer (SCLC). NSCLC can be divided into squamous cell carcinoma and non-squamous cell carcinoma.
2) Approximately 25-40% of patients with NSCLC present with locally advanced (Stage III) disease which has a low 5-year survival rate. Around 30% present with unresectable Stage III disease.
3) The KEYNOTE-189 trial showed that pembrolizumab plus chemotherapy improved overall survival compared to placebo plus chemotherapy as first-line treatment for Stage IV non-squamous NSCLC, regardless of PD-L1 expression
This document discusses a clinical trial comparing cisplatin-based chemoradiotherapy to cetuximab-based chemoradiotherapy for p16-positive oropharyngeal cancer. The trial found that while overall toxicity was similar between the two arms, serious adverse events were significantly more common with cisplatin treatment. However, patients receiving cisplatin chemoradiotherapy experienced significantly better 2-year overall survival and lower recurrence rates compared to those receiving cetuximab chemoradiotherapy. The findings suggest that for HPV-positive oropharyngeal cancer, cisplatin chemoradiotherapy provides excellent survival outcomes despite greater toxicity risks compared to cetuximab chemoradiotherapy.
The document summarizes key findings from three clinical trials (IMpower110, IMpower150, IMpower130) evaluating the efficacy and safety of atezolizumab in combination with chemotherapy or as monotherapy for the first-line treatment of non-small cell lung cancer. The IMpower110 trial found that atezolizumab monotherapy improved overall survival compared to chemotherapy in patients with high PD-L1 expression. The IMpower150 trial evaluated atezolizumab plus chemotherapy versus chemotherapy alone or with bevacizumab. The IMpower130 trial compared atezolizumab plus two chemotherapy regimens. Overall, the results showed that adding atezolizumab to chemotherapy provided clinical benefit over chemotherapy
The document discusses lung cancer subtypes and molecular features that can guide treatment. It provides statistics on the distribution of histology types among lung cancer cases. It also summarizes several key studies investigating targeted therapies such as EGFR TKIs versus chemotherapy as first-line treatment for advanced non-small cell lung cancer, noting improved progression-free survival with TKIs in patients with EGFR mutations. Molecular testing is increasingly important for determining personalized treatment approaches in lung cancer.
Join Dr. Emily Chan presentation on the latest research and treatments for colorectal cancer patients presented at the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago.
1) Lung cancer tumors display a high number of somatic mutations, rendering them more immunogenic. The presence of tumor-infiltrating FOXP3+ regulatory T-cells is associated with recurrence in early-stage non-small cell lung cancer patients.
2) Brambilla et al. (2016) found that lymphocyte infiltration has a prognostic effect in resectable non-small cell lung cancer.
3) Immunotherapies targeting CTLA-4 and PD-1/PD-L1 have shown efficacy in lung cancer treatment, with nivolumab demonstrating improved overall survival compared to docetaxel in previously treated squamous and non-squamous non-small cell lung cancer
3.Case Based Moderation Slidedeck 110_130_150.pptxBipineshSansar
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This document provides an overview of neoadjuvant and adjuvant therapy strategies for patients with resectable pancreatic cancer. It summarizes results from several key clinical trials evaluating different chemotherapy regimens in the neoadjuvant and adjuvant settings. It also discusses ongoing trials investigating newer treatment approaches for resectable and borderline resectable disease.
The document discusses immunotherapy options for nonmetastatic non-small cell lung cancer (NSCLC). It summarizes results from several clinical trials evaluating the addition of immunotherapy to standard chemotherapy and radiation therapy regimens. A key trial, CheckMate 816, found that neoadjuvant nivolumab plus chemotherapy significantly improved pathologic complete response rates and event-free survival compared to chemotherapy alone in patients with resectable stage IB-IIIA NSCLC. Based on these results, nivolumab was approved by the FDA in combination with chemotherapy in the neoadjuvant setting for resectable NSCLC tumors. The document provides an overview of evolving treatment approaches incorporating immunotherapy to improve outcomes for nonmetastatic NSCLC
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Lung cancer is a leading cause of cancer death. Immunotherapy using immune checkpoint inhibitors that target proteins like PD-1 and PD-L1 has shown promise in treating lung cancer. A study presented at ASCO 2015 found that treatment with the PD-L1 inhibitor atezolizumab resulted in improved survival for NSCLC patients with higher levels of PD-L1 expression on tumor cells compared to docetaxel chemotherapy. Another study showed nivolumab, a PD-1 inhibitor, improved survival over docetaxel as a treatment for advanced non-squamous NSCLC after chemotherapy, with greater benefit seen in patients with higher PD-L1 expression levels. These results suggest PD-L1 expression can help identify
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This document summarizes new approaches for head and neck cancer, including robotic surgery, proton radiotherapy, biomarkers like HPV and PD-L1 status, genomic profiling, and immunotherapy like nivolumab and pembrolizumab. It shows that immunotherapy such as nivolumab has better outcomes for HPV-positive head and neck cancer patients compared to standard chemotherapy. PD-L1 expression is also associated with better outcomes from pembrolizumab and nivolumab treatment. Combining cetuximab with chemotherapy improves survival compared to chemotherapy alone in recurrent/metastatic head and neck cancer. Pembrolizumab demonstrates superior overall survival compared to standard of care for recurrent/metastatic head and neck
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1) Bevacizumab is an anti-angiogenic drug that has shown efficacy in improving progression-free survival and overall survival when added to chemotherapy for first-line treatment of non-squamous non-small cell lung cancer based on results from phase 3 trials.
2) The IMpower150 trial found that adding atezolizumab, an immune checkpoint inhibitor, to bevacizumab and chemotherapy further improved progression-free and overall survival compared to bevacizumab and chemotherapy alone in previously untreated non-squamous non-small cell lung cancer.
3) The NEJ026 trial found that adding bevacizumab to erlotinib, an EGFR tyrosine kinase inhibitor, significantly improved
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This document summarizes information about three cancer vaccines - MAGE-A3, Stimuvax (L-BLP25, Tecemotide), and Lucanix (Belagenpumatucel-L). It discusses past and ongoing clinical trials of these vaccines in non-small cell lung cancer (NSCLC), including trial designs, results, and potential efficacy in patient subgroups. Key information presented includes Phase 3 trial results for Stimuvax showing a possible survival benefit in patients receiving concurrent chemotherapy and radiation, and evidence that Belagenpumatucel-L may benefit certain NSCLC patient subgroups based on retrospective analyses.
5-Year Survival of Non-Small Cell Lung Cancer Patients after Radical Surgery Significantly Depended on Phase Transition “Early-Invasive Cancer”, Lymph Node Metastases and Cell Ratio Factors
1) Adjuvant chemotherapy reduces breast cancer mortality by 17-33% according to meta-analyses, with anthracycline-based regimens being more effective than CMF.
2) For HER2-positive early breast cancer, adjuvant chemotherapy plus trastuzumab is the standard of care, improving disease-free and overall survival compared to chemotherapy alone.
3) For endocrine-responsive early breast cancer, the absolute benefit of chemotherapy depends on risk factors; genomic signatures can help identify patients most likely to benefit from chemotherapy in addition to endocrine therapy.
1) Adjuvant chemotherapy reduces breast cancer mortality by 17-33% according to meta-analyses, with anthracycline-based regimens being more effective than CMF.
2) For HER2-positive early breast cancer, adjuvant chemotherapy plus trastuzumab is the standard of care, improving disease-free and overall survival compared to chemotherapy alone.
3) For endocrine-responsive early breast cancer, the absolute benefit of chemotherapy depends on risk factors; genomic signatures can help identify patients most likely to benefit from chemotherapy in addition to endocrine therapy.
This document provides an expert summary on adjuvant and neoadjuvant therapy options for HER2-positive early-stage breast cancer. It discusses trials demonstrating improved disease-free and overall survival with adjuvant trastuzumab-based regimens. For lower-risk early-stage HER2-positive breast cancer, 1 year of adjuvant trastuzumab with or without chemotherapy is recommended. For higher-risk disease, newer neoadjuvant and adjuvant regimens incorporating dual anti-HER2 blockade or antibody-drug conjugates are discussed. The document also reviews toxicity profiles of different therapeutic approaches.
Mercurius is named after the roman god mercurius, the god of trade and science. The planet mercurius is named after the same god. Mercurius is sometimes called hydrargyrum, means ‘watery silver’. Its shine and colour are very similar to silver, but mercury is a fluid at room temperatures. The name quick silver is a translation of hydrargyrum, where the word quick describes its tendency to scatter away in all directions.
The droplets have a tendency to conglomerate to one big mass, but on being shaken they fall apart into countless little droplets again. It is used to ignite explosives, like mercury fulminate, the explosive character is one of its general themes.
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CCO_Biomarkers_Lung_Cancer_ASCO_Slides_2.pptx
1. Evolving Understanding of Biomarkers of
Response to Immune Checkpoint Inhibition
in NSCLC
Supported by an educational grant from Lilly. For further information
concerning Lilly grant funding, visit www.lillygrantoffice.com.
2. About These Slides
Please feel free to use, update, 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
permissions@clinicaloptions.com for details
Slide credit: clinicaloptions.com
3. Faculty
Edward S. Kim, MD, FACP
Chair, Solid Tumor Oncology and
Investigational Therapeutics
Donald S. Kim Distinguished Chair for
Cancer Research
Levine Cancer Institute
Atrium Health
Charlotte, North Carolina
Leora Horn, MD, MSc, FRCPC
Ingram Associate Professor of Cancer
Research
Director, Thoracic Oncology Research
Program
Assistant Vice Chairman for Faculty
Development
Vanderbilt Ingram Cancer Center
Nashville, Tennessee
4. Faculty Disclosures
Edward S. Kim, MD, FACP, has disclosed that he has received consulting fees
from AstraZeneca, Boehringer Ingelheim, Lilly, Merck, Roche, and Takeda.
Leora Horn, MD, MSc, FRCPC, has disclosed that she has received consulting
fees from Amgen, AstraZeneca, Bayer, EMD Serono, Genentech, Incyte, Merck,
Pfizer, and Xcovery and funds for research support from Boehringer Ingelheim,
Bristol-Myers Squibb, and Xcovery.
5. Evolution of Therapy in Lung Cancer
NSCLC was once considered a single disease, until distinct subtypes, characteristics identified[1-4]
NSCLC subtype characteristics are clinically relevant for treatment planning from diagnosis[1]
Traditional View
Present View
NSCLC
SCLC
Histologic Breakdown
(eg, SQ, NSQ, large cell,
adenocarcinoma)
Molecular Pathology
(eg, EGFR, ALK, ROS1)
PD-L1 Expression Level[5]
Lung
Cancer
≥ 50%
Tumor Mutational Burden[6]
≥ 10 mut/Mb
< 10 mut/Mb
≥ 1-49%
< 1%
1. Cooper. Pathology. 2011;43:103. 2. Langer. J Clin Oncol. 2010;28:5311. 3. Galon. Immunity. 2013;39:11.
4. Pao. Lancet Oncol. 2011;12:175. 5. Krigsfeld. AACR 2017. Abstr CT143. 6. Hellmann. NEJM. 2018;378:2093. Slide credit: clinicaloptions.com
6. Increased Clinical Benefit of Immunotherapy Across
PD-L1 Expression Levels in Second-line NSCLC
OS benefit observed across the PD-L1 spectrum, including < 1% PD-L1 expression[1]
Enhanced benefit with increasing PD-L1 expression[1-3]
Docetaxel
(n = 343)
Pembrolizumab
(n = 690)
PD-L1 Expression
≥ 50%
1-49%
Overall (PD-L1+ only)
KEYNOTE-010‡[3]
OS HR
< 1%
Docetaxel
(n = 612)
Atezolizumab
(n = 613)
PD-L1 Expression
TC1/2/3 or IC1/2/3†
TC0 and IC0
Overall
TC3 or IC3
TC2/3 or IC2/3
OAK (ITT1225)†[2]
OS HR
1
0.77
0.84
0.80
0.45
0.64
0.2 2
Checkmate 017/057*[1]
(Pooled Analysis)
PD-L1 Expression
Docetaxel
(n = 427)
Nivolumab
(n = 427)
OS HR
≥ 1%
< 1%
Overall
≥ 10%
≥ 50%
≥ 5%
0.25 0.5 1 2
0.67
0.78
0.72
0.47
0.42
0.51
0.1 1 10
Not included
0.53
0.76
0.67
*Unstratified HR. Pooled analysis of 2 trials with NSQ and SQ histologies. NSQ: N = 582; SQ: N = 272. †Unstratified HR for TC0 and IC0. Stratified HR for overall and other
PD-L1 subgroups. Overall, NSQ: 74%; SQ: 26%. NSQ and SQ histologies were pooled. ‡In patients who received pembro 2 mg/kg, NSQ: 70%; SQ: 22%. In patients who
received pembro 10 mg/kg, NSQ: 71%; SQ: 23%. In patients who received docetaxel, NSQ: 70%; SQ: 19%. Pooled analysis of NSQ and SQ histologies.
1. Horn. JCO. 2017;35:3924. 2. Fehrenbacher. JTO. 2018;13:1156. 3. Herbst. Lancet. 2016;387:1540. Slide credit: clinicaloptions.com
7. TMB and Tumor PD-L1 Expression Identify Distinct and
Independent Populations of NSCLC
29%
71%
CheckMate 227: TMB and Tumor PD-L1 Expression in
All TMB-Evaluable Patients (n = 1004)*
PD-L1 Expression (%)
TMB
(No.
of
Mutations/Mb)
0
20
40
60
80
100
160
120
140
0 20 40 60 80 100
TMB ≥ 10 mut/Mb
(n = 299)
PD-L1 < 1%
PD-L1 ≥ 1%
29%
71%
PD-L1 < 1%
PD-L1 ≥ 1%
TMB < 10 mut/Mb
(n = 380)
CheckMate 227: TMB and Tumor PD-L1 Expression in
NIVO + IPI and CT Arms
*Dots may represent multiple data points, in particular for PD-L1 < 1%. Line is relationship between TMB and PD-L1 expression as described by a linear regression.
Hellmann. AACR 2018. Abstr CT077. Slide credit: clinicaloptions.com
8. PD-L1 IHC: Expression Heterogeneity and Potential for
Sampling Error
Biopsy Core 1
Biopsy Core 2
18g needle =
800 µm
Slide courtesy of Ben Solomon via Michael Boyer. Slide credit: clinicaloptions.com
9. Pembrolizumab
(n = 154)
Chemotherapy
(n = 151)
Median OS, mos
(95% CI)
30.0
(18.3-NR)
14.2
(9.8-19.0)
12-mo OS, % 70.3 54.8
24-mo OS, % 51.5 34.5
Paradigm Shift in First-line Therapy for Advanced NSCLC:
Pembro Is Superior to CT in Patients With TPS ≥ 50%
KEYNOTE-024: open-label, randomized phase III study
Mos
154
151
136
123
121
107
112
88
106
80
89
61
83
55
22
16
5
5
HR: 0.63
(95% CI: 0.47-0.86;
P = .002)
OS
(%)
96
70
52
31
0
0
100
90
80
70
60
50
40
30
20
10
0
33
0 3 6 9 12 15 18 21 24 27 30
Patients
at Risk, n
Pembro
CT
Effective crossover rate from CT to anti–PD-L1 therapy: 62.3% (82 patients crossed over
to pembrolizumab and 12 received anti–PD-L1 therapy outside of crossover).
Data cutoff: July 10, 2017.
Reck. NEJM. 2016;375:1823. Brahmer. WCLC 2017. Abstr OA 17.06.
Pembrolizumab 200 mg IV Q3W
for up to 35 cycles
(n = 154)
Platinum-Doublet CT
(histology based) for 4-6 cycles
(n = 151)
*≥ 50% tumor cell staining using 22C3 companion diagnostic IHC assay.
Chemotherapy-naive,
stage IV NSCLC;
PD-L1 selected (TPS ≥ 50%*);
ECOG PS 0/1;
no actionable EGFR/ALK
mutations; no untreated CNS
mets or active autoimmune
disease requiring treatment
(N = 305)
Stratified by ECOG PS (0 vs 1), histology
(squamous vs nonsquamous), and
enrollment site
Slide credit: clinicaloptions.com
10. Similar Efficacy With First-line Atezolizumab in Patients
With NSCLC and High PD-L1 Expression (TC3 or IC3)
IMpower110: randomized phase III study
Untreated LA or
metastatic NSCLC of
any histology;
PD-L1 ≥ 1% on TC or IC*;
no sensitizing EGFR or ALK
alterations; ECOG PS 0/1;
no untreated or unstable
CNS mets or pneumonitis
requiring tx
(N = 572)
Atezolizumab 1200 mg Q3W
until PD
(n = 107)
Platinum-Doublet CT
(histology based)
for 4-6 cycles
(n = 98)
HR: 0.59 (95% CI: 0.40-0.89; P = .0106)
Median OS: 20.2 mos
(95% CI: 16.5-NE)
Median OS: 13.1 mos
(95% CI: 7.4-16.5)
Herbst. SITC 2019. Abstr O81.
Data cutoff: September 10, 2018. Median follow-up: 15.7 mos (range: 0-35).
No crossover permitted.
*PD-L1 tumor cell staining on TC or IC using VENTANA SP142 IHC assay.
WT efficacy populations: TC1/2/3 or IC1/2/3, n = 554; TC2/3 or IC2/3,
n = 328; TC3 or IC3, n = 205.
Stratified by sex, ECOG PS, histology,
and tumor PD-L1 status
Mos
OS
(%)
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 30 36
2 8 14 20 26 32 38
4 10 16 22 28 34
Patients at Risk, n
Atezolizumab 107 94 85 80 66 61 48 40 34 25 18 16 11 7 6 5 2
Chemotherapy 98 89 75 65 50 40 33 28 19 12 9 7 6 4 3 3 3 1
Atezolizumab
Chemotherapy
Censored
Slide credit: clinicaloptions.com
11. Limited OS Benefit With Atezolizumab in Patients With
NSCLC and Low PD-L1 Expression (TC1/2/3 or IC1/2/3)
HR: 0.83
(95% CI: 0.65-1.07; P = .1481*)
*For descriptive purposes only.
Data cutoff: September 10, 2018. Median follow-up: 13.4 mos (range: 0-35).
Atezolizumab
(n = 277)
Chemotherapy
(n = 277)
Median OS, mos
(95% CI)
17.5
(12.8-23.1)
14.1
(11.0-16.6)
6-mo OS, % 76.2 75.7
12-mo OS, % 57.6 54.3
Herbst. SITC 2019. Abstr O81.
Mos
OS
(%)
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 30 36
2 8 14 20 26 32 38
4 10 16 22 28 34
Patients at Risk, n
Atezolizumab 277 252 226 204 170 134 93 74 58 37 22 17 11 7 6 5 2
Chemotherapy 277 254 223 199 153 108 79 63 43 24 10 7 6 4 3 3 3 1
Slide credit: clinicaloptions.com
12. Pembrolizumab Not As Impressive in PD-L1 ≥ 1%: KEYNOTE-042
The PD-L1 ≥ 50% subgroup is the main driver of OS benefit in PD-L1-positive patients
KEYNOTE-042: Pembrolizumab Not
as Impressive in PD-L1 ≥ 1%
PD-L1 ≥ 50% subgroup is main driver of OS benefit in
PD-L1–positive patients
OS: PD-L1 TPS ≥ 50%
0
20
40
60
80
100
0 6 12 18 24 30 36 42
44.7%
OS
(%)
OS: PD-L1 TPS ≥ 1%
0 6 12 18 24 30 36 42
0
20
40
60
80
100
OS
(%)
39.3%
Events,
n
Median OS, Mos
(95% CI)
Pembrolizumab 371 16.7 (13.9-19.7)
Chemotherapy 199 12.1 (11.3-13.3)
Lopes. ASCO 2018. Abstr LBA4. Mok. Lancet. 2019;393:1819. *Exploratory analysis; no alpha allocated to this comparison.
HR: 0.69
(95% CI: 0.56-0.85; P = .0003)
HR: 0.81
(95% CI: 0.71-0.93; P = .0018)
34.6%
OS: PD-L1 TPS ≥ 1-49%*
HR: 0.92
(95% CI: 0.77-1.11)
Mos
Mos
0
20
40
60
80
100
0 6 12 18 24 30 36 42
OS
(%)
28.0%
26.5%
30.1%
Events,
n
Median OS, Mos
(95% CI)
Pembrolizumab 157 22.0 (15.4-24.9)
Chemotherapy 199 12.2 (10.4-14.2)
Events,
n
Median OS, Mos
(95% CI)
Pembrolizumab 214 13.4 (1.7-18.2)
Chemotherapy 239 12.1 (11.0-14.0)
Slide credit: clinicaloptions.com
13. *Nonsquamous: pem + cis or carbo Q3W for
≤ 4 cycles with optional maintenance (CT: pem;
nivolumab + CT: nivolumab + pem); squamous: gem +
cis or carbo Q3W for ≤ 4 cycles. †1 patient randomized
as < 1% PD-L1 and subsequently determined to have
≥ 1% PD-L1 expression.
CheckMate 227: Nivolumab ± Ipilimumab in NSCLC
Open-label, multipart, randomized phase III trial
Patients with
stage IV or recurrent
NSCLC, no previous
systemic treatment,
no known sensitizing
EGFR/ALK alterations,
ECOG PS 0/1
(N = 1739)
NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W
(n = 187)
NIVO 360 mg Q3W + Histology-Based CT*
(n = 177)
Histology-Based CT*
(n = 186)
Stratified by histology
(squamous vs nonsquamous)
NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W
(n = 396)
NIVO 240 mg Q2W
(n = 396)
Histology-Based CT*
(n = 397)
Part 1b:
< 1% PD-L1
expression†
(n = 550)
Part 1a:
≥ 1% PD-L1
expression
(n = 1189)
Up to 2 yrs for IO
Coprimary endpoints: for
nivolumab + ipilimumab vs
CT, PFS in patients with
high TMB (≥ 10 mut/Mb),
OS in patients with ≥ 1%
PD-L1 expression
Secondary endpoints: PFS,
OS in patients with PD-L1
< 1% receiving nivolumab +
CT vs CT; OS in patients
with PD-L1 ≥ 50% receiving
nivolumab vs CT
Hellmann. NEJM. 2018;378:2093. Hellmann. NEJM. 2019;381:2020. Peters. ESMO 2019. Abstr LBA7128. Slide credit: clinicaloptions.com
14. NIVO + IPI NIVO CT
Median OS, mos 17.1 15.7 14.9
HR (vs CT)* 0.79
(97.72% CI:
0.65-0.96)
0.88
(95% CI:
0.75-1.04)
OS
CheckMate 227: OS and PFS in Patients With ≥ 1% PD-L1
Expression
Slide credit: clinicaloptions.com
NIVO + IPI NIVO CT
Median OS, mos 5.1 4.2 5.6
HR (vs CT)†
(95% CI)
0.82
(0.69-0.97)
0.99
(0.84-1.17)
PFS by BICR
100
80
60
40
20
0
OS
(%)
Mos
0 3 45
6 27
9 30
12 15 36
18 39
21 42
33
24
Patients at Risk, n
NIVO + IPI
NIVO
CT
396
396
397
341
330
358
295
299
306
264
265
250
244
220
218
212
201
190
190
176
166
165
153
141
153
139
126
145
129
112
129
115
93
91
70
57
41
36
22
9
10
6
1
2
1
0
0
0
NIVO + IPI
NIVO
CT
63%
57%
56%
40%
36%
33%
100
80
60
40
20
0
PFS
(%)
Mos
0 3 6 27
9 30
12 15 36
18 39
21 33
24
396
396
397
221
199
253
158
136
130
130
104
63
108
85
44
91
68
32
83
56
23
73
47
17
65
42
12
62
37
12
47
24
8
31
15
2
7
3
1
0
0
0
NIVO + IPI
NIVO
CT
33%
26%
19%
22%
14%
7%
Hellmann. NEJM. 2019;381:2020. Peters. ESMO 2019. Abstr LBA7128.
*HR for NIVO + IPI vs NIVO: 0.90 (95% CI: 0.76-1.07). †HR for NIVO + IPI vs NIVO: 0.83 (95% CI: 0.71-0.97). 35% receiving NIVO + IPI, 44% receiving NIVO,
and 54% receiving CT received subsequent systemic tx; subsequent IO was received by 6%, 8%, and 43%, respectively.
15. CheckMate 227: 3-Yr OS Update in Patients With NSCLC
and PD-L1 ≥ 1%
Ramalingam. ASCO 2020. Abstr 9500.
Data cutoff: February 28, 2020. Minimum follow-up for OS: 37.7 mos. Among patients who were alive at 3 yrs, 35% receiving NIVO + IPI, 45%
receiving NIVO + chemo, and 76% receiving CT received subsequent systemic therapy; subsequent immunotherapies were received by 13%, 21%,
and 71%, respectively; subsequent chemotherapy was received by 28%, 33%, and 30%, respectively.
Mos
OS
(%)
NIVO + IPI
NIVO
CT
396
396
397
341
330
358
295
299
306
264
265
250
244
220
218
212
201
190
190
176
166
165
153
141
153
139
126
145
129
112
132
119
98
54
4
4
0
0
0
124
112
87
121
108
80
97
83
62
67
45
32
27
21
13
NIVO + IPI
(n = 396)
NIVO
(n = 396)
CT
(n = 397)
Median OS, mos 17.1 15.7 14.9
HR (vs CT)
(95% CI)
0.79
(0.67-0.93)
0.88
(0.77-1.06)
57%
56%
36%
33%
29%
22%
40%
33%
NIVO + IPI
NIVO
CT
63%
100
80
60
40
0
20
0 3 45
6 27
9 30
12 15 36
18 39
21 42
33
24 48 51
Slide credit: clinicaloptions.com
16. CheckMate 227: Efficacy in Patients With NSCLC and
PD-L1 ≥ 50%
Median DoR with NIVO + IPI, NIVO and CT was 31.8, 17.5, and 5.8 mos, respectively
PFS by BICR
ORR by BICR OS
ORR
(%)
n/N:
36.9
8.8
35.6
2.1
33.3
4.7
32.2
35.4
PR
CR
6 12 18 24 30 36 42
3 9 15 21 27 33 39
OS
(%)
0
0 45
100
80
60
40
20
Mos
54%
67%
61%
PFS
(%)
0
0 39
100
80
60
40
20
Mos
6 12 18 24 30 36
3 9 15 21 27 33
15%
41%
34%
NIVO + IPI
NIVO + IPI
NIVO
NIVO
CT
CT
NIVO + IPI
(n = 205)
NIVO
(n = 214)
CT
(n = 192)
Median OS,
mos (95% CI)
21.2
(15.5-38.2)
18.1
(14.4-22.1)
14.0
(10.0-18.6)
HR (vs CT)
(95% CI)
0.70
(0.55-0.90)
0.79
(0.63-1.01)
NIVO + IPI
(n = 205)
NIVO
(n = 214)
CT
(n = 192)
Median PFS,
mos (95% CI)
6.7
(4.5-11.0)
5.6
(4.2-8.3)
5.6
(4.6-6.6)
HR (vs CT)
(95% CI)
0.62
(0.49-0.79)
0.75
(0.59-0.95)
36%
48%
42%
5%
31%
20%
NIVO + IPI NIVO CT
79/214 68/192
91/205
Hellmann. NEJM. 2019;381:2020. Peters. ESMO 2019. Abstr LBA7128.
0
10
20
30
40
50
44.4
Slide credit: clinicaloptions.com
17. CheckMate 003: 5-Yr OS With Nivolumab
Phase 1 trial of nivolumab in patients with advanced NSCLC of any histology after
1-5 lines of prior systemic therapy
100
80
60
40
20
0
0 1 2 3 4 5 6 7 8
129 49 27 20 17 16 3 1 0
Yrs
Patients
at Risk, n
OS
(%)
1-yr OS: 42%
2-yr OS: 24%
3-yr OS: 18% 5-yr OS: 16%
n = 3 deaths in Yrs 3-5 due to PD; n = 1 censored for OS prior to 5 yrs (OS: 58.2+ mos).
Brahmer. AACR 2017. Abstr CT077.
Overall (N = 129)
Median OS, Mos
(95% CI)
9.9
(7.8-12.4)
Slide credit: clinicaloptions.com
18. KEYNOTE-189: First-line Pembrolizumab + CT in
Advanced Nonsquamous NSCLC
Randomized, double-blind, international phase III study
Gandhi. NEJM. 2018;378:2078.
Patients with previously
untreated stage IIB/IV
nonsquamous NSCLC;
any PD-L1 status;
no actionable
EGFR/ALK mutations;
ECOG PS 0/1;
no untreated CNS mets or
pneumonitis requiring tx
(N = 616)
Primary endpoints: OS, PFS by BICR
Secondary endpoints: ORR, DoR, safety
Pembrolizumab 200 mg Q3W +
Plt*/pemetrexed† Q3W
(n = 410)
Placebo Q3W +
Plt*/pemetrexed† Q3W
(n = 206)
4 cycles
Pembrolizumab +
Pemetrexed
Q3W
Placebo+
Pemetrexed
Q3W
Stratified by PD-L1 TPS (≥ 1% vs < 1%), platinum agent (carboplatin
vs cisplatin), smoking history (never vs former/current)
*Carboplatin AUC 5 or cisplatin 75 mg/mm2. †500 mg/m2. ‡Up to total of
35 cycles. ‡If verified PD, then crossover to pembrolizumab allowed.
No
PD
No
PD‡
12-mo rate
34.1%
17.3%
PFS
0
20
40
60
80
100
0 3 6 9 12 15 18 21
Mos
PFS
(%)
HR: 0.52
(95% CI: 0.43-0.64; P < .00001)
Median PFS,
Mos
Pembro + CT 8.8
Pbo + CT 4.9
Median OS,
Mos
Pembro + CT NR
Pbo + CT 11.3
12-mo rate
69.2%
49.4%
OS
0
20
40
60
80
100
0 3 6 9 12 15 18 21
OS
(%)
HR: 0.49
(95% CI: 0.38-0.64; P < .001)
Slide credit: clinicaloptions.com
19. IMpower150: Addition of Atezolizumab to Carbo/Pac +
Bevacizumab in Advanced NSCLC
Randomized phase III study
Patients with stage IV or
recurrent, chemotherapy-
naive* nonsquamous NSCLC
(PD on or intolerance to
targeted agents allowed);
available tumor tissue
(N = 1202)
Atezolizumab 1200 mg IV Q3W +
Carboplatin/Paclitaxel
(n = 510)
Carboplatin/Paclitaxel Q3W +
Bevacizumab 15 mg/kg IV Q3W
(n = 336; control arm)
Atezolizumab 1200 mg IV Q3W +
Carboplatin/Paclitaxel Q3W +
Bevacizumab 15 mg/kg IV Q3W
(n = 356)
Atezolizumab
until PD or loss of
benefit and/or
bevacizumab
until PD
Atezolizumab
Bevacizumab
Atezolizumab +
Bevacizumab
Stratified by sex, PD-L1 expression, liver mets
4-6 cycles
Socinski. NEJM. 2018;378:2288.
Maintenance therapy
(no crossover allowed)
Primary endpoints: PFS, OS
Secondary endpoints: PFS (IRF), ORR, OS at Yrs 1 and 2, QoL, safety, PK
Slide credit: clinicaloptions.com
*Patients with a sensitising EGFR or ALK aberration must have
PD or intolerance with ≥ 1 approved targeted therapies.
21. Randomized, multicenter, open-label phase III study
Coprimary endpoints: PFS (investigator assessed), OS in ITT-WT population
Secondary endpoints: PFS and OS in ITT and by PD-L1 expression in ITT and ITT-WT populations;
ORR and DoR in ITT-WT population; safety
IMpower130: Atezolizumab ± Carboplatin/
nab-Paclitaxel in Advanced Nonsquamous NSCLC
West. Lancet Oncol. 2019;20:924.
Atezolizumab +
Carboplatin + nab-Paclitaxel
3-wk cycles x 4-6
(n = 483 ITT; 451 ITT-WT)
Patients with CT-naive
stage IV nonsquamous
NSCLC, ECOG PS 0/1,
EGFR mut or ALK+
enrolled if PD on
targeted therapy
(N = 724*;
n = 679 ITT-WT)
Stratified by sex, baseline liver metastases,
tumor PD-L1 expression
*n = 723 included in ITT population. Carboplatin AUC 6 Q3W, nab-paclitaxel 100 mg/m2 QW,
paclitaxel 200 mg/m2 Q3W, atezolizumab 1200 mg Q3W, pemetrexed 500 mg/m2 Q3W. Crossover
to atezolizumab permitted for patients in chemotherapy alone arm enrolled before 6/15/2016,
with confirmed PD status.
Carboplatin + nab-Paclitaxel
3-wk cycles x 4-6
(n = 240 ITT; 228 ITT-WT)
Atezolizumab
until PD
BSC or
Pemetrexed
until PD
OS
OS
(%)
Atezo + CT
CT
18.6
13.9
Median
OS, Mos
451
228
Patients,
n
63.1
55.5
12-Mo
OS, %
HR: 0.79
(95% CI: 0.64-0.98; P = .033)
100
90
80
70
60
50
40
30
20
10
0
33
0 3 6 9 12 15 18 21 27
24 30
Mos After Randomization
39.6
30.0
24-Mo
OS, %
Patients at Risk, n
Atezo + CT
CT
451
228
400
190
351
161
305
136
268
119
194
90
129
58
75
31
40
13
12
3
4
0
Slide credit: clinicaloptions.com
22. Phase III KEYNOTE-407: Carboplatin + Paclitaxel/nab-
Paclitaxel ± Pembrolizumab in Advanced Squamous NSCLC
Randomized, double-blind phase III trial
Primary endpoint: PFS by RECIST v1.1 (BICR), OS
Secondary endpoints: ORR and DoR by RECIST v1.1 (BICR), safety
Paz-Ares. NEJM. 2018;379:2040.
Pembrolizumab + Carboplatin +
Paclitaxel or nab-Paclitaxel
3-wk cycles x 4
(n = 278)
Patients with untreated stage IV
squamous NSCLC, ECOG PS 0/1,
available tumor biopsy for PD-L1
assessment, no brain mets, and
no pneumonitis requiring
systemic steroids
(N = 559)
Stratified by PD-L1 TPS (< 1% vs ≥ 1%), taxane (paclitaxel
vs nab-paclitaxel), region (east Asia vs other)
Carboplatin AUC 6 Q3W, nab-paclitaxel 100 mg/m2 QW, paclitaxel 200 mg/m2 Q3W, pembrolizumab 200 mg Q3W.
*Upon confirmation of PD and safety criteria by BICR, optional crossover could occur during combination or monotherapy.
Placebo + Carboplatin +
Paclitaxel or nab-Paclitaxel
3-wk cycles x 4
(n = 281)
Pembrolizumab
up to 31 cycles
Placebo
up to 31 cycles
Pembrolizumab
up to 35 cycles
Crossover
allowed*
PD
Slide credit: clinicaloptions.com
23. KEYNOTE-407: OS
23
278 256 188 124 17
281 246 175 93 16
62
45
0
0
2
4
Patients at Risk, n
Pembrolizumab + CT
Placebo + CT
OS at Interim Analysis 2 (ITT)
Paz-Ares. NEJM. 2018;379:2040.
HR: 0.64
(95% CI: 0.49-0.85; P = .0008)
Mos
OS
(%)
100
80
60
40
20
0
0 3 6 9 12 15 18 21
15.9 (13.2-NE)
11.3 (9.5-14.8)
Pembrolizumab + CT
Placebo + CT
30.6
42.7
Events,
%
Median OS,
Mos (95% CI)
Slide credit: clinicaloptions.com
24. 243
185
221
165
186
127
153
83
92
34
117
56
0
1
79
26
Patients at Risk, n
Pembro + CT
CT
Mos
OS
(%) 100
80
60
40
20
0
0 3 6 9 12 15 18 33
Pooled Analysis of KEYNOTE-021G, 189, and 407: OS in
Patients Without Tumor PD-L1 Expression (TPS < 1%)
Events, n
Median OS,
Mos (95% CI)
Pembrolizumab + CT 112 19.0 (15.2-24.0)
CT 110 11.0 (9.2-13.5)
Data cutoff: KN021G, December 1, 2017; KN189, September 21, 2018; KN407, April 3, 2018.
Paz-Ares. ESMO. 2019. Abstr 4311.
49
16
29
7
13
5
2
4
21 24 27 30
66%
52%
47%
29%
HR: 0.56 (95% CI: 0.43-0.73)
Slide credit: clinicaloptions.com
25. CheckMate 227: 3-Yr OS Update in Patients With NSCLC
and PD-L1 < 1%
Data cutoff: February 28, 2020. Minimum follow-up for OS: 37.7 mos. Among patients who were alive at 3 yrs, 49% receiving NIVO + IPI, 38%
receiving NIVO + chemo, and 78% receiving CT received subsequent systemic therapy; subsequent immunotherapies were received by 12%, 12%,
and 74%, respectively; subsequent chemotherapy was received by 46%, 35%, and 33%, respectively.
Ramalingam. ASCO 2020. Abstr 9500.
OS
(%)
Mos
177 159 139 119 102 88 67 60 0
78
NIVO + CT 0
4
34
39
42
48 25 15
Patients at Risk, n
187 165 142 120 110 100 87 80 0
NIVO + IPI 73 6
16
23
43
59
69 65 62
186 164 135 107 92 74 49 41 0
62
CT 3
9
12
17
27
35 33 29
NIVO + IPI
(n = 187)
NIVO + CT
(n = 177)
CT
(n = 186)
Median OS, mos 17.2 15.2 12.2
HR (vs CT)
(95% CI)
0.64
(0.51-0.81)
0.82
(0.66-1.03)
51%
60%
59%
23%
40%
35%
15%
20%
34%
NIVO + IPI
NIVO + CT
CT
100
80
60
40
0
20
0 3 45
6 27
9 30
12 15 36
18 39
21 42
33
24 48 51
Slide credit: clinicaloptions.com
26. Primary endpoint: OS
Secondary endpoints: PFS, ORR, efficacy by tumor PD-L1 expression
Phase III CheckMate 9LA: Nivolumab + Ipilimumab + CT
Randomized, open-label, phase III study
Reck. ASCO 2020. Abstr 9501.
Data cutoff for interim analysis: October 3, 2019. Minimum follow-up: 8.1 mos for OS; 6.5 mos for all other endpoints.
Data cutoff for updated analysis: March 9, 2020. Minimum follow-up: 12.7 mos for OS and 12.2 mos for all other endpoints.
*PD-L1 assessed by 28-8 IHC assay. †Patients unevaluable for PD-L1 were
stratified to PD-L1 < 1% and capped to 10% of all randomized patients.
‡NSQ: platinum + pemetrexed; SQ: carboplatin + nab-paclitaxel.
Patients with
stage IV or recurrent
NSCLC, no previous
systemic tx, no
sensitizing EGFR/ALK
alterations, ECOG PS 0/1
(N = 719)
NIVO 360 mg Q3W + IPI 1 mg/kg Q6W
+ CT‡ Q3W (2 cycles)
(n = 361)
CT‡ Q3W (4 cycles)
Optional pemetrexed maintenance (NSQ)
(n = 358)
Stratified by PD-L1 expression* (≥ 1% vs < 1%†),
sex, and histology (squamous vs nonsquamous)
Until PD,
unacceptable
toxicity,
or for 2 yrs for
IO
OS
Mos
OS
(%)
20
40
60
80
100
0
0 3 6 9 12 15 18 21 24 27 30
NIVO + IPI + CT
CT
81%
73%
63%
47%
Patients at Risk, n
NIVO + IPI + CT
CT
361
358
326
319
292
260
250
208
227
166
153
116
86
67
33
26
10
11
1
0
0
0
HR: 0.66 (95% CI: 0.55-0.80)
Patients,
n
Median OS,
Mos (95% CI)
NIVO + IPI + CT
CT
361
358
15.6 (13.9-20.0)
10.9 (9.5-12.6)
Slide credit: clinicaloptions.com
27. Primary endpoint: OS
Secondary endpoints: PFS, ORR, efficacy by
tumor PD-L1 expression and bTMB, safety
CCTG BR.34: Durvalumab/Tremelimumab ±
Chemotherapy in Stage IV NSCLC
Leighl. ASCO 2020. Abstr 9502. NCT03057106.
*NSQ: platinum + pemetrexed; SQ: platinum + gemcitabine. †NSQ: durvalumab +
pemetrexed; SQ: durvalumab. Crossover not permitted.
Randomized, open-label phase II study
Patients with stage IV A
(high risk) or IVB metastatic
NSCLC (any histology);
no prior CT for adv disease;
no sensitizing EGFR/ALK
alterations; ECOG PS 0/1;
no untreated brain mets or
prior autoimmune disease
(N = 301)
Durvalumab 1500 mg IV +
Tremelimumab 75 mg IV
Q28D
(n = 150)
Durvalumab 1500 mg IV +
Tremelimumab 75 mg IV +
Platinum-Doublet CT* Q21D
(n = 151)
Stage (IVA vs IVB), histology (squamous vs nonsquamous), and
smoking status (never vs current vs former)
4 cycles
Durvalumab
until PD
Durvalumab ±
Pemetrexed
until PD
Mos
OS
(%)
100
80
60
40
20
0
0 4 8 12 16 20 24 28
Durva/Trem
Durva/Trem + CT
14.1 (10.6-18.3)
16.6 (12.6-19.1)
Median OS,
Mos (90% CI)
Durva/Trem
Durva/Trem
+ CT
150
151
125
129
85
100
63
79
37
44
11
18
3
9
1
2
HR (stratified): 0.88
(95% CI: 0.67-1.16; log-rank P = .46)
Patients at Risk, n
Slide credit: clinicaloptions.com
29. Or Is Carboplatin/Paclitaxel/Bevacizumab/Atezolizumab
a Good Option?
*Prevalence for ALK rearrangement and EGFR mutation out of EGFR/ALK+ only (n = 108).
†Prevalence for ex19del and L858R out of EGFR mutation only (n = 80).
‡Must have PD with or intolerance to ≥ 1 approved targeted therapies.
§n = 6 with both EGFR mutation and ALK rearrangement.
‖Other EGFR mutations include L861Q, G719X, S7681, exon 20 insertion, T790M, and other.
Data cutoff: September 15, 2017.
IMpower150 Populations n (%)
ITT (including EGFR/ALK+) 800 (100)
EGFR/ALK+ only*‡ 108 (14)
ALK rearrangement*§ 34 (31)
EGFR mutation*§ 80 (74)
Exon 19 deletion or L858R†‖ 59 (74)
ITT-WT 692 (87)
Liver metastases 110 (14)
No liver metastases 690 (86)
Median PFS, Mos
ABCP BCP
8.3 6.8
9.7 6.1
8.3 5.9
10.2 6.9
10.2 6.1
8.3 6.8
8.2 5.4
8.3 7.0
0.61
0.2 2.0
1.0
In favor of
BCP
HR
In favor of
ABCP
0.59
0.40
0.64
0.62
0.65
0.41
0.60
Kowanetz. AACR 2018. Slide credit: clinicaloptions.com
31. CheckMate 227: Median OS by Subgroup and in All
Randomized Patients
No consistent correlation between OS with NIVO + IPI vs chemo and by PD-L1 or TMB
alone or in combination
Median OS, Mos
NIVO + IPI CT
HR HR (95% CI)
(n = 583) (n = 583)
Randomized groups Stratified Stratified
PD-L1 status
All randomized (N = 1166) 17.1 13.9 0.73
< 1% (n = 373) 17.2 12.2 0.62
≥ 1% (n = 793) 17.1 14.9 0.79*
Additional exploratory subgroups analyses†‡ Unstratified Unstratified
PD-L1 status
1-49% (n = 396) 15.1 15.1 0.94
≥ 50% (n = 397) 21.2 14.0 0.70
TMB§
(mut/Mb)
Low, < 10 (n = 380) 16.2 12.6 0.75
High, ≥ 10 (n = 299) 23.0 16.4 0.68
0.25 0.5 1 2
NIVO + IPI CT
*97.72% CI. †Subgroup analyses should be interpreted with caution as patients were not stratified by TMB or PD-L1 ≥ or < 50%. ‡Not controlled by randomization.
§Unstratified HR for NIVO + IPI vs CT in TMB-evaluable (n = 679) and nonevaluable (n = 487) patients was 0.74 (95% CI: 0.61-0.88) and 0.74 (95% CI: 0.60-0.92), respectively.
Peters. ESMO 2019. LBA7128. Slide credit: clinicaloptions.com
32. Risk of Death and Progression in Combined bTMB and
PD-L1 TC Subgroups
Leighl. ASCO 2020. Abstr 9502.
Survival in Patients with PD-L1 TC ≥ 25%,
bTMB < 20 or ≥ 20 mutations/Mb
PFS in Patients with PD-L1 TC ≥ 25%,
bTMB < 20 or ≥ 20 mutations/Mb
bTMB < 20,
PD-L1 < 25%
bTMB < 20,
PD-L1 ≥ 25%
bTMB ≥ 20,
PD-L1 < 25%
bTMB ≥ 20,
PD-L1 ≥ 25%
102
48
42
15
0.65 (0.45-0.92)
0.6 (0.35-1.04)
0.82 (0.45-1.50)
1.22 (0.37-4.01)
.79
bTMB < 20,
PD-L1 < 25%
bTMB < 20,
PD-L1 ≥ 25%
bTMB ≥ 20,
PD-L1 < 25%
bTMB ≥ 20,
PD-L1 ≥ 25%
102
48
42
15
0.93 (0.62-1.40)
0.83 (0.42-1.62)
1.18 (0.59-2.37)
0.74 (0.07-7.63)
.76
Combined bTMB and
PD-L1 TC Groups n HR (90% CI) P Value
bTMB and PD-L1 TC:
Combined bTMB and
PD-L1 TC Groups n HR (90% CI) P Value
bTMB and PD-L1 TC:
DT +
Chemo
Better
DT
Better
0.01 0.1 1 10 100
DT +
Chemo
Better
DT
Better
0.01 0.1 1 10 100
Slide credit: clinicaloptions.com
33. KEYNOTE 189: tTMB Does Not Predict for Clinical
Outcomes After Chemo-IO
Pembro + Pem + Platinum
No association between tTMB and PD-L1
(r = -0.08, two-sided P = .27)
tTMB-Evaluable Population (N = 293)
HR: 0.64 (95% CI: 0.46-0.88)
TMB ≥ 175 mut/exome (n = 134)
HR: 0.64 (95% CI: 0.38-1.07)
TMB ≥ 150 Mut/exome (n = 159)
HR: 0.68 (95% CI: 0.43-1.09)
Garassino. WCLC 2019. Abstr OA04.06.
Placebo + CT
Pembrolizumab + CT
PD-L1 TPS (%)
tTMB
(mut/exome)
Patients at Risk, n
111 93 84 78 70 47 19 4 0
41 36 25 21 15 11 6 1 0
Mos
OS
(%)
0 4 8 12 16 20 24 28 32
100
80
60
40
0
20
Patients at Risk, n
100 83 78 74 67 44 19 4 0
34 30 21 18 13 9 5 0 0
Mos
OS
(%)
0 4 8 12 16 20 24 28 32
100
80
60
40
0
20
1000
300
100
30
1000
0 10 20 30 40 50 60 70 80 90 100
Nonresponder
Responder
Slide credit: clinicaloptions.com
Mos
OS
(%)
0 4 8 12 16 20 24 28 32
100
80
60
40
0
20
35. STK11/LKB1 Genomic Alterations in Nonsquamous
NSCLC: Study Design and Patient Characteristics at BL
Multicenter, international, retrospective study
Cohorts
‒ Cohort 1: metastatic nonsquamous NSCLC
treated with first-line pembrolizumab +
carboplatin/pemetrexed with available genomic
profiling, including STK11
‒ Cohort 2: metastatic STK11 and/or KEAP1-
mutant nonsquamous NSCLC treated with
first-line carboplatin/pemetrexed prior to
regulatory approval of pembrolizumab +
carboplatin/pemetrexed
Alive ≥ 14 days after cycle 1, Day 1
All nonsynonymous STK11 and KEAP1
mutations and biallelic deletions included
Sensitizing EGFR mutations and ALK
translocations excluded
Skoulidis. ASCO 2019. Abstr 102.
Characteristic
PCP
(n = 452)
PCP*
(n = 131)
PC
(n = 169)
STK11 status, n
Mutant
WT
NA
117†
335‡
0
117
14 (KEAP1Mut)
0
142
21 (KEAP1Mut)
6 (KEAP1Mut)
ECOG PS, n (%)
0/1
2/3
NA
379 (84)
59 (13)
56 (3)
113 (86)
17 (13)
1 (1)
132 (78)
30 (18)
7 (4)
Brain mets, n (%)
No
Yes
NA
286 (63)
142 (31.5)
24 (5.5)
80 (61)
47 (36)
4 (3)
111 (66)
44 (26)
14 (8)
Histology, n (%)
LUAD
NSCLC-NOS
Other
421 (93)
18 (4)
13 (3)
122 (93)
4 (3)
5 (4)
154 (91)
10 (6)
5 (3)
*Cohort receiving PCP with available KEAP1 data. †26%. ‡74%.
Slide credit: clinicaloptions.com
36. Integration of STK11, KEAP1 Onco-Genotypes Identifies
Nonsq NSCLC Subgroup With Inferior Outcomes With CIT
STK11MUT and/or KEAP1MUT: PR/CR, 21.5%; SD, 38.5%; PD, 40%
Skoulidis. ASCO 2019. Abstr 102.
OS
Mos
PFS
(%)
OS
(%)
Mos
PFS, Mos
STK11WT and KEAP1WT (n = 73) 8.4
STK11MUT and/or KEAP1MUT (n = 66) 3.6
PFS
OS, Mos
STK11WT and KEAP1WT (n = 74) 20.4
STK11MUT and/or KEAP1MUT (n = 66) 10.6
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 30 36
0
10
20
30
40
50
60
70
80
90
100
0 6 12 18 24 30 36
HR: 2.39 (95% CI: 1.58-3.63;
log rank P < .0001)
HR: 2.0 (95% CI: 1.18-3.41;
log rank P = .01)
Slide credit: clinicaloptions.com
37. Log-rank P = .0005
Skoulidis. ASCO 2019. Abstr 102. Slide credit: clinicaloptions.com
PFS OS
Integration of STK11 and KEAP1 Genomic Alterations
With TMB
Mos
PFS
(%)
100
80
60
40
20
0
24
0 6 12 18
STK11WT; KEAP1WT; TMBHIGH
STK11WT; KEAP1WT; TMBLOW
STK11MUT and/or KEAP1MUT; TMBHIGH
STK11MUT and/or KEAP1MUT; TMBLOW
Median
PFS, Mos
12.4
4.5
4.1
3.6
Log-rank P = .03
Mos
OS
(%)
100
80
60
40
20
0
36
0 6 12 18
STK11WT; KEAP1WT; TMBHIGH
STK11WT; KEAP1WT; TMBLOW
STK11MUT and/or KEAP1MUT; TMBHIGH
STK11MUT and/or KEAP1MUT; TMBLOW
Median
OS, Mos
28.9
20.4
10.7
9.1
24 30
38. MYSTIC: No Clear Predictive Role for STK11mut
*Mutation-evaluable patients.
Rizvi. WCLC 2019. Abstr OA04.07.
Durvalumab vs CT Durvalumab + Tremelimumab vs CT
Mos to Event or Censor
Probability
of
OS
0 5 10 15 20 25 30 35
1.0
0.8
0.6
0.4
0
0.2 D STK11mut
CT STK11mut
D STK11wt
CT STK11wt
D + T STK11mut
CT STK11mut
D + T STK11wt
CT STK11wt
STK11wt D (n = 257) CT (n = 268)
mOS, mos 13.3 13.1
(95% CI) (10.0-16.2) (11.6-15.1)
HR vs CT
(95% CI)
0.98
(0.80-1.19)
Mos to Event or Censor
Probability
of
OS
0 5 10 15 20 25 30 35
1.0
0.8
0.6
0.4
0
0.2
Mos to Event or Censor
Probability
of
OS
0 5 10 15 20 25 30 35
1.0
0.8
0.6
0.4
0
0.2
Mos to Event or Censor
Probability
of
OS
0 5 10 15 20 25 30 35
1.0
0.8
0.6
0.4
0
0.2
STK11mut D (n = 55) CT (n = 41)
mOS, mos 10.3 6.7
(95% CI) (6.1-14.8) (4.5-10.0)
HR vs CT
(95% CI)
0.64
(0.41-1.0)
STK11wt D + T (n = 257) CT (n = 268)
mOS, mos 11.3 13.1
(95% CI) (9.7-13.7) (11.6-15.1)
HR vs CT
(95% CI)
1.05
(0.86-1.27)
STK11mut D + T (n = 51) CT (n = 41)
mOS, mos 4.4 6.7
(95% CI) (3.3-9.2) (4.5-10.1)
HR vs CT
(95% CI)
0.76
(0.48-1.21)
Slide credit: clinicaloptions.com
39. N mOS, Mos
(95% CI)
G12C 74 5.2 (4.3-6.9)
G12D 62 5.7 (4.6-7.6)
G12V 54 4.1 (3.1-5.1)
Others 78 4.9 (4.0-6.9)
N mOS, Mos
(95% CI)
G12C 62 3.8 (2.7-6.8)
G12D 58 1.2 (1.2-3.2)
G12V 41 5.7 (2.8-10.8)
Others 57 2.7 (1.6-3.3)
STK11 Mutation Associated With Worse Prognosis in
KRAS-Positive NSCLC
PFS by
First-line
CT + IO
PFS by
2nd-4th line
IO
KRAS G12C or G12V Mutated NSLC by
Concomitant STK11 Status
KRAS-Mutated NSLC by Mutation Subtype
Tamiya. ASCO 2020. Abstr 9589.
1.0
0.8
0.6
0.4
0.2
0
Probability
of
PFS
0 3 6 9 12 15
Mos
1.0
0.8
0.6
0.4
0.2
0
Probability
of
PFS
0 3 6 9 12 15
Mos
G12C vs G12D, P = .02
G12C vs Others, P < .01
G12V vs G12D, P = .01
G12V vs Others, P < .01
1.0
0.8
0.6
0.4
0.2
0
Probability
of
PFS
0 3 6 9 12 15
Mos
N mPFS, Mos
(95% CI)
STK11(-) 117 4.9 (4.1-5.7)
STK11(+) 11 5.5 (0.7-9.5)
HR: 0.80
(95% CI: 0.44-1.64;
P = .50)
1.0
0.8
0.6
0.4
0.2
0
Probability
of
PFS
0 3 6 9 12 15
Mos
N mPFS, Mos
(95% CI)
STK11(-) 89 5.7 (3.3-9.3)
STK11(+) 14 1.8 (1.0-5.8)
HR: 1.97
(95% CI: 1.06-3.41;
P = .02)
Slide credit: clinicaloptions.com
40. Current Paradigm for Immunotherapy in Advanced
NSCLC Without an Actionable Mutation
For PD-L1 low (1%-49%) or
negative (< 1%), SoC is
combination ICI + CT
For ≥ 50% PD-L1, choice of
single-agent ICI or ICI + CT
‒ Single-agent ICI approved for
≥ 1% PD-L1 but not broadly
recommended by experts
Lim. Immune Netw. 2020;20:e10. Slide credit: clinicaloptions.com
PD-L1 high
(≥ 50%)
PD-(L)1 inhibitor
or CT +
PD-(L)1 inhibitor
PD-L1 low (1%-49%)
or negative (< 1%)
Squamous
histology
Nonsquamous
histology
CT +
PD-1 inhibitor
CT +
PD-(L)1 inhibitor
In May 2020, nivolumab/ipilimumab approved for first-line treatment of advanced
NSCLC with ≥ 1% PD-L1, and nivolumab/ipilimumab plus 2 cycles of platinum-
doublet chemotherapy approved for first-line treatment of advanced NSCLC
without EGFR or ALK genomic aberrations
41. Lack of Efficacy With Immune Checkpoint Inhibition in
EGFR Mutation–Positive NSCLC
Phase II study of pembrolizumab in patients with PD-L1–positive EGFR-mutated advanced
NSCLC (planned N = 25); stopped for futility at 11 patients
Lisberg. J Thorac Oncol. 2018;13:1138. Slide credit: clinicaloptions.com
Best Response for Target Lesions Subsequent Therapies and Reasons
for Treatment Discontinuation
*AE led to discontinuation.
†Completed tx, under surveillance.
‡Died while on erlotinib
(1 by fatal pneumonitis).
§Report of EGFR mut was in error.
EGFR-WT§
20
10
0
-10
-20
-30
-40
-50
Change
From
Baseline
(%)
*
†
Mos
0 2 4 6 8 10 12
*
*
* ‡
‡
†
Pembrolizumab
No therapy
Erlotinib
Afatinib
Chemotherapy
Clinical trial
PD
Tx 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 mut was in error.
EGFR-WT‡
42. Potential Toxicity With Sequential Use of
Immunotherapy Followed by a TKI
Retrospective 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 mos of ICI, 24% developed a severe irAE;
conversely, no severe irAEs were identified if osimertinib was given before ICI
Schoenfeld. Ann Oncol. 2019;30:839. Slide credit: clinicaloptions.com
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 G3 pneumonitis Y Y
2 Pembrolizumab + CT* 21 23 15 G3 pneumonitis N Y
3 Nivolumab +
ipilimumab
392 22 167 G3 pneumonitis Y Y
4 Pembrolizumab 126 28 14 G3 colitis Y N
5 Pembrolizumab 126 314 15 G3 pneumonitis Y Y
6 Nivolumab 68 39 39 G4 hepatitis Y N
*Carboplatin plus pemetrexed.
43. Conclusions
Checkpoint inhibitors have become first-line standard of care as monotherapy or in
combination with chemotherapy for a cohort of lung cancer patients
PD-L1 can be used to select patients for single-agent pembrolizumab, atezolizumab,
or nivolumab + ipilimumab
Combination checkpoint inhibitor therapy lacks a good biomarker but is standard of
care in patients with PD-L1 < 50%
STK11 and KEAP1 genomic alterations are associated with poor clinical outcomes
with chemotherapy and immunotherapy in nonsquamous NSCLC
Ongoing phase III trials are comparing checkpoint inhibition to chemotherapy or in
combination with chemotherapy in patients in the neoadjuvant setting and may help
us answer some open questions
44. clinicaloptions.com/oncology
clinicaloptions.com/LungTool
clinicaloptions.com/immuneAETool
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