CheckMate 77T: A Double‑Blind Phase 3 Trial of Neoadjuvant ...
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Presented at the 2021 Florida Society of Clinical Oncology (FLASCO) Spring Session, Kissimmee, FL, April 16-17, 2021. Reused with permission from the American Society of Clinical Oncology (ASCO). This abstract was accepted and previously presented at the 2020 ASCO Virtual Meeting. All rights reserved. Email: [email protected] Copies of this e-poster obtained through QR codes are for personal use only and may not be reproduced without written permission of the authors. CheckMate 77T: A Double‑Blind Phase 3 Trial of Neoadjuvant Nivolumab Plus Chemotherapy Followed by Adjuvant Nivolumab in Resectable Non‑Small Cell Lung Cancer Jhanelle Gray, 1 * Tina Cascone, 2 Mariano Provencio, 3 Boris Sepesi, 2 Shun Lu, 4 Nivedita Aanur, 5 Sunney Li, 5 Jonathan Spicer 6 1 Moffitt Cancer Center, Tampa, FL, USA; 2 The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 3 Hospital Universitario Puerta de Hierro, Madrid, Spain; 4 Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China; 5 Bristol Myers Squibb, Princeton, NJ, USA; 6 McGill University, Montreal, Quebec, Canada *On behalf of the authors Background Unmet medical needs in early or localized resectable non‑small cell lung cancer (NSCLC) • Lung cancer is the leading cause of cancer death worldwide 1 — NSCLC comprises the majority of lung cancer cases (~ 85% in the United States) 2 — Up to 20%–25% of patients with NSCLC present with early or localized disease amenable to surgery 3 • Although potentially curative for stage IIA‑IIIB disease, surgery historically results in 5‑year overall survival (OS) rates < 50% 4 — A rational approach to improve OS in these patients is to eradicate micrometastatic disease and minimize relapse risk with adjuvant or neoadjuvant therapy 5,6 — However, conventional neoadjuvant or adjuvant chemotherapy provides only a 5% absolute improvement in OS at 5 years 7,8 — New therapeutic approaches for patients with early or localized NSCLC are needed Immune checkpoint inhibition with nivolumab • Programmed death (PD)‑1, an immune checkpoint molecule that is highly expressed on activated T cells, regulates T‑cell function during inflammation by binding to its ligands, PD ligand 1 (PD‑L1) and PD ligand 2 (PD‑L2), on tissue cells and antigen‑presenting cells 9 — Engagement of PD‑1 on tumor‑infiltrating T cells by PD‑L1 or PD‑L2 on tumor cells leads to T‑cell inhibition and tumor immune evasion 9 • Nivolumab is a fully human PD‑1 immune checkpoint inhibitor antibody that blocks the binding of PD‑1 to PD‑L1 / PD‑L2, thereby abrogating negative signaling and restoring antitumor T‑cell activity (Figure 1) 10–12 — Nivolumab, in combination with ipilimumab, is indicated in the United States for the first‑line treatment of adult patients with metastatic NSCLC whose tumors express PD‑L1 ( ≥ 1%) as determined by an FDA‑approved test, with no EGFR or ALK genomic tumor aberrations 13 — Nivolumab as monotherapy is approved in the United States, 13 the European Union, 14 and other countries for the treatment of patients with metastatic NSCLC whose disease has progressed on or after chemotherapy, as well as for the treatment of patients with other tumors in various countries Figure 1. Nivolumab mechanism of action Tumor cell Dendritic Cell T cell Nivolumab: PD‑1 receptor‑blocking antibody T‑cell receptor T‑cell receptor MHC IFNγR IFNγ MHC PD‑L1 PD‑L2 PD‑L1 B7 CD28 PD‑L2 PD‑1 Shp‑2 Shp‑2 PD‑1 PD‑1 PD‑1 Other NFκB PI3K IFNγ, interferon gamma; IFNγR, interferon gamma receptor; NFκB, nuclear factor kappa‑light‑chain‑enhancer of activated B cells; PI3K, phosphoinositide 3‑kinase; Shp‑2, Src homology 2 domain‑containing phosphatase‑2. Study Rationale Nivolumab combined with chemotherapy as perioperative therapy • Combining cytotoxic chemotherapy with a PD‑1 inhibitor therapy may augment the antitumor immune response through cell-death induced increased tumor antigenicity and reduction of Treg‑mediated immune suppression 15,16 • Early phase trials using major pathologic response (MPR; ≤ 10% viable tumor in resected tumor specimens) indicate that nivolumab‑based regimens have the potential to deepen pathological responses and extend survival in this setting 17-19 • Neoadjuvant nivolumab plus chemotherapy followed by adjuvant nivolumab exhibited encouraging response and preliminary survival outcomes in patients with resectable stage IIIA NSCLC in the single‑arm phase 2 NADIM trial (Figure 2) 19 — No patients withdrew preoperatively due to toxicity 19 — 18‑month progression‑free survival (PFS): 81% (95% CI: 61%‑91%) 19 — 18‑month OS: 91% (95% CI: 73%‑97%) 19 Figure 2. Efficacy of neoadjuvant nivolumab plus chemotherapy followed by adjuvant nivolumab in stage IIIA resectable NSCLC (NADIM study) 19 Nivolumab + Chemo a,b (N = 46; ITT) Surgery d (n = 41) Nivolumab (n = 37) Objective response c , n (%) ITT (N = 46) CR 2 (4) PR 32 (70) SD 12 (26) Pathological response, n (%) [95% CI] Resected Population (n = 41) MPR e 34 (83) [68-93] pCR 24 (59) [42-74] > 10% residual tumor 7 (17) [7-32] Survival, % (95% CI) ITT (N = 46) 18‑month PFS 81 (61-91) 18‑month OS 91 (73-97) a Nivolumab 360 mg + paclitaxel 200 mg / m 2 + carboplatin AUC6 Q3W for 3 cycles. b Intent‑to‑treat population. All patients received 3 cycles except 1 who decided to withdraw and only received 2 cycles. c RECIST 1.1. d Five patients were not resected after neoadjuvant treatment. e MPR including pCR. AUC, area under the curve; CR, complete response; ITT, intent to treat; MPR, major pathological response; pCR, pathological complete response; PR, partial response; SD, stable disease. Study Design • CheckMate 77T (NCT04025879) is a phase 3, randomized, double‑blind trial evaluating neoadjuvant nivolumab plus chemotherapy followed by adjuvant nivolumab vs neoadjuvant placebo plus chemotherapy followed by adjuvant placebo in resectable early stage NSCLC (Figure 3) • Key inclusion and exclusion criteria are listed in Table 1 Figure 3. CheckMate 77T study design Key Eligibility Criteria • Resectable, stage IIA-IIIB (T3N2) NSCLC • No prior treatment • ECOG PS 0-1 Primary Endpoint: EFS by blinded independent central review (BICR) Key Secondary Endpoints: OS; pCR rate by blinded independent pathology review (BIPR); MPR rate by BIPR; AEs; SAEs Nivolumab 360 mg + histology‑based platinum doublet chemotherapy a Q3W up to 4 doses Placebo + histology‑based platinum doublet chemotherapy a Q3W up to 4 doses Nivolumab 480 mg Q4W for 1 year Placebo Q4W for 1 year Surgery Surgery R 1:1 (N = 452) a Squamous histology: carboplatin + paclitaxel, or cisplatin + docetaxel. Non‑squamous histology: carboplatin + pemetrexed, cisplatin + pemetrexed, or carboplatin + paclitaxel. AE, adverse event; ECOG PS, Eastern Cooperative Oncology Group performance status; EFS, event‑free survival; MPR, major pathological response; OS, overall survival; pCR, pathological complete response; SAE, serious adverse event. Table 1. Select CheckMate 77T inclusion and exclusion criteria Inclusion criteria Exclusion criteria Histologically confirmed, stage IIA‑IIIB, resectable NSCLC ECOG PS 0‑1 Eligibility for complete lung cancer resection EGFR or ALK mutations Brain metastasis Prior systemic anti‑cancer treatment or radiotherapy in NSCLC Active, known, or suspected autoimmune disease ECOG PS, Eastern Cooperative Oncology Group performance status. Key Endpoints Primary endpoint • EFS by BICR Secondary endpoints • OS • pCR rate by BIPR • MPR rate by BIPR • Safety and tolerability Study Sites and Dates • 115 study sites in 21 countries (Figure 4) • Study start date: September 2019 • Estimated primary completion date: May 2023 • Estimated study completion date: September 2024 Figure 4. CheckMate 77T study sites Canada, Mexico, Puerto Rico, United States Argentina, Brazil Australia China, Japan, Russia, Taiwan Belgium, Czech Republic, France, Germany, Ireland, Italy, Netherlands, Poland, Romania, Spain, United Kingdom References 1. Globocan 2018. http://gco.iarc.fr/today/data/ factsheets/cancers/15‑Lungfact‑sheet.pdf. Accessed April 18, 2020. 2. Noone AM, et al. SEER Cancer Statistics Review, 1975– 2015, National Cancer Institute. https://seer.cancer. gov/csr/1975_2015/. Accessed April 18, 2020. 3. Datta D, Lahiri B. Chest. 2003;123:2096–2103. 4. Siegel RL, Miller KD, Jemal A. CA Cancer J Clin. 2015;65:5‑29. 5. Douillard JY. EJC Suppl. 2013;11:131–136. 6. McElnay P, Lim E. J Thorac Dis. 2014;6(suppl 2):S224– S227. 7. NSCLC Meta‑analyses Collaborative Group. Lancet. 2010;375:1267‑1277. 8. NSCLC Meta‑analyses Collaborative Group. Lancet. 2014;383:1561‑1571. 9. Pardoll DM. Nat Rev Cancer. 2012;12:252–264. 10. Brahmer JR, et al. J Clin Oncol. 2010;28:3167–3175. 11. Topalian SL, et al. N Engl J Med. 2012;366:2443–2454. 12. Wang C, et al. Cancer Immunol Res. 2014;2:846–856. 13. OPDIVO® (nivolumab) [package insert]. Princeton, NJ: Bristol‑Myers Squibb Company; March 2020. 14. OPDIVO® [summary of product characteristics]. Uxbridge, UK: Bristol‑Myers Squibb Company; March 2020. 15. Bracci L, et al. Cell Death Differ. 2014;21:15−25. 16. Roselli M, et al. Oncoimmunology. 2013;2:e27025. 17. Reuss JE, et al. Poster presentation at the ASCO Annual Meeting; May 31‑June 4, 2019; Chicago IL. Abstract# 8524. 18. Cascone T, et al. Oral presentation at the ASCO Annual Meeting; May 31‑June 4, 2019; Chicago IL. Abstract# 8504. 19. Provencio M, et al. Oral presentation at the World Conference on Lung Cancer; September 7‑10; Barcelona, Spain. Abstract# OA13.05. Acknowledgments • The patients and families for making this trial possible • The contributions of the study teams from the sites involved in the trial • The protocol manager for this study, Jonathan Steuve • Bristol Myers Squibb (Princeton, NJ) and ONO Pharmaceutical Company Ltd. (Osaka, Japan) • The study was supported by Bristol Myers Squibb • All authors contributed to and approved the presentation; writing assistance was provided by Scarlett Geunes‑Boyer, PhD, of Bio Connections, funded by Bristol Myers Squibb To request a copy of this poster: Scan QR code via a barcode reader application QR codes are valid for 30 days after the congress presentation date. Scientific Content on Demand
Transcript of CheckMate 77T: A Double‑Blind Phase 3 Trial of Neoadjuvant ...
Presented at the 2021 Florida Society of Clinical Oncology (FLASCO) Spring Session, Kissimmee, FL, April 16-17, 2021. Reused with permission from the American Society of Clinical Oncology (ASCO). This abstract was accepted and previously presented at the 2020 ASCO Virtual Meeting. All rights reserved.
Email: [email protected] Copies of this e-poster obtained through QR codes are for personal use only and may not be reproduced without written permission of the authors.
CheckMate 77T: A Double‑Blind Phase 3 Trial of Neoadjuvant Nivolumab Plus Chemotherapy Followed by Adjuvant Nivolumab in Resectable Non‑Small Cell Lung CancerJhanelle Gray,1* Tina Cascone,2 Mariano Provencio,3 Boris Sepesi,2 Shun Lu,4 Nivedita Aanur,5 Sunney Li,5 Jonathan Spicer6
1Moffitt Cancer Center, Tampa, FL, USA; 2The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 3Hospital Universitario Puerta de Hierro, Madrid, Spain; 4Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China; 5Bristol Myers Squibb, Princeton, NJ, USA; 6McGill University, Montreal, Quebec, Canada
*On behalf of the authors
BackgroundUnmet medical needs in early or localized resectable non‑small cell lung cancer (NSCLC)• Lung cancer is the leading cause of cancer death worldwide1
— NSCLC comprises the majority of lung cancer cases (~ 85% in the United States)2
— Up to 20%–25% of patients with NSCLC present with early or localized disease amenable to surgery3
• Although potentially curative for stage IIA‑IIIB disease, surgery historically results in 5‑year overall survival (OS) rates < 50%4
— A rational approach to improve OS in these patients is to eradicate micrometastatic disease and minimize relapse risk with adjuvant or neoadjuvant therapy5,6
— However, conventional neoadjuvant or adjuvant chemotherapy provides only a 5% absolute improvement in OS at 5 years7,8
— New therapeutic approaches for patients with early or localized NSCLC are needed
Immune checkpoint inhibition with nivolumab• Programmed death (PD)‑1, an immune checkpoint molecule that is
highly expressed on activated T cells, regulates T‑cell function during inflammation by binding to its ligands, PD ligand 1 (PD‑L1) and PD ligand 2 (PD‑L2), on tissue cells and antigen‑presenting cells9
— Engagement of PD‑1 on tumor‑infiltrating T cells by PD‑L1 or PD‑L2 on tumor cells leads to T‑cell inhibition and tumor immune evasion9
• Nivolumab is a fully human PD‑1 immune checkpoint inhibitor antibody that blocks the binding of PD‑1 to PD‑L1 / PD‑L2, thereby abrogating negative signaling and restoring antitumor T‑cell activity (Figure 1)10–12
— Nivolumab, in combination with ipilimumab, is indicated in the United States for the first‑line treatment of adult patients with metastatic NSCLC whose tumors express PD‑L1 (≥1%) as determined by an FDA‑approved test, with no EGFR or ALK genomic tumor aberrations13
— Nivolumab as monotherapy is approved in the United States,13 the European Union,14 and other countries for the treatment of patients with metastatic NSCLC whose disease has progressed on or after chemotherapy, as well as for the treatment of patients with other tumors in various countries
Figure 1. Nivolumab mechanism of action
Tumor cellDendritic
CellT cell
Nivolumab: PD‑1 receptor‑blocking antibody
T‑cellreceptor
T‑cellreceptor
MHC
IFNγR
IFNγ
MHC
PD‑L1
PD‑L2
PD‑L1
B7CD28
PD‑L2
PD‑1
Shp‑2Shp‑2
PD‑1
PD‑1
PD‑1
OtherNFκB
PI3K
IFNγ, interferon gamma; IFNγR, interferon gamma receptor; NFκB, nuclear factor kappa‑light‑chain‑enhancer of activated B cells; PI3K, phosphoinositide 3‑kinase; Shp‑2, Src homology 2 domain‑containing phosphatase‑2.
Study RationaleNivolumab combined with chemotherapy as perioperative therapy• Combining cytotoxic chemotherapy with a PD‑1 inhibitor therapy may
augment the antitumor immune response through cell-death induced increased tumor antigenicity and reduction of Treg‑mediated immune suppression15,16
• Early phase trials using major pathologic response (MPR; ≤ 10% viable tumor in resected tumor specimens) indicate that nivolumab‑based regimens have the potential to deepen pathological responses and extend survival in this setting17-19
• Neoadjuvant nivolumab plus chemotherapy followed by adjuvant nivolumab exhibited encouraging response and preliminary survival outcomes in patients with resectable stage IIIA NSCLC in the single‑arm phase 2 NADIM trial (Figure 2)19
— No patients withdrew preoperatively due to toxicity19
— 18‑month progression‑free survival (PFS): 81% (95% CI: 61%‑91%)19
— 18‑month OS: 91% (95% CI: 73%‑97%)19
Figure 2. Efficacy of neoadjuvant nivolumab plus chemotherapy followed by adjuvant nivolumab in stage IIIA resectable NSCLC (NADIM study)19
Nivolumab + Chemoa,b
(N = 46; ITT)
Surgeryd
(n = 41)
Nivolumab(n = 37)
Objective responsec, n (%) ITT (N = 46)
CR 2 (4)
PR 32 (70)
SD 12 (26)
Pathological response, n (%) [95% CI]
Resected Population
(n = 41)
MPRe 34 (83) [68-93]
pCR 24 (59) [42-74]
> 10% residual tumor 7 (17) [7-32]
Survival, % (95% CI) ITT (N = 46)
18‑month PFS 81 (61-91)
18‑month OS 91 (73-97)
aNivolumab 360 mg + paclitaxel 200 mg / m2 + carboplatin AUC6 Q3W for 3 cycles. bIntent‑to‑treat population. All patients received 3 cycles except 1 who decided to withdraw and only received 2 cycles. cRECIST 1.1. dFive patients were not resected after neoadjuvant treatment. eMPR including pCR.AUC, area under the curve; CR, complete response; ITT, intent to treat; MPR, major pathological response; pCR, pathological complete response; PR, partial response; SD, stable disease.
Study Design• CheckMate 77T (NCT04025879) is a phase 3, randomized, double‑blind
trial evaluating neoadjuvant nivolumab plus chemotherapy followed by adjuvant nivolumab vs neoadjuvant placebo plus chemotherapy followed by adjuvant placebo in resectable early stage NSCLC (Figure 3)
• Key inclusion and exclusion criteria are listed in Table 1
Figure 3. CheckMate 77T study design
Key Eligibility Criteria• Resectable, stage IIA-IIIB (T3N2) NSCLC
• No prior treatment
• ECOG PS 0-1
Primary Endpoint: EFS by blinded independent central review (BICR)
Key Secondary Endpoints: OS; pCR rate by blinded independent pathology review (BIPR); MPR rate by BIPR; AEs; SAEs
Nivolumab 360 mg +
histology‑based platinum doublet chemotherapya
Q3W up to 4 doses
Placebo+
histology‑based platinum doublet chemotherapya
Q3W up to 4 doses
Nivolumab 480 mg
Q4W for 1 year
Placebo
Q4W for 1 year
Surgery Surgery
R1:1
(N = 452)
aSquamous histology: carboplatin + paclitaxel, or cisplatin + docetaxel.Non‑squamous histology: carboplatin + pemetrexed, cisplatin + pemetrexed, or carboplatin + paclitaxel.AE, adverse event; ECOG PS, Eastern Cooperative Oncology Group performance status; EFS, event‑free survival; MPR, major pathological response; OS, overall survival; pCR, pathological complete response; SAE, serious adverse event.
Table 1. Select CheckMate 77T inclusion and exclusion criteria
Inclusion criteria Exclusion criteria
Histologically confirmed, stage IIA‑IIIB, resectable NSCLC
ECOG PS 0‑1
Eligibility for complete lung cancer resection
EGFR or ALK mutations
Brain metastasis
Prior systemic anti‑cancer treatment or radiotherapy in NSCLC
Active, known, or suspected autoimmune disease
ECOG PS, Eastern Cooperative Oncology Group performance status.
Key EndpointsPrimary endpoint• EFS by BICR
Secondary endpoints• OS
• pCR rate by BIPR
• MPR rate by BIPR
• Safety and tolerability
Study Sites and Dates• 115 study sites in 21 countries (Figure 4)
• Study start date: September 2019
• Estimated primary completion date: May 2023
• Estimated study completion date: September 2024
Figure 4. CheckMate 77T study sites
Canada, Mexico, Puerto Rico,United States
Argentina,Brazil Australia
China, Japan,Russia, Taiwan
Belgium, Czech Republic, France, Germany, Ireland, Italy, Netherlands, Poland, Romania,
Spain, United Kingdom
References1. Globocan 2018. http://gco.iarc.fr/today/data/
factsheets/cancers/15‑Lungfact‑sheet.pdf. Accessed April 18, 2020.
2. Noone AM, et al. SEER Cancer Statistics Review, 1975–2015, National Cancer Institute. https://seer.cancer.gov/csr/1975_2015/. Accessed April 18, 2020.
3. Datta D, Lahiri B. Chest. 2003;123:2096–2103.4. Siegel RL, Miller KD, Jemal A. CA Cancer J Clin.
2015;65:5‑29.5. Douillard JY. EJC Suppl. 2013;11:131–136.6. McElnay P, Lim E. J Thorac Dis. 2014;6(suppl 2):S224–
S227.7. NSCLC Meta‑analyses Collaborative Group. Lancet.
2010;375:1267‑1277.8. NSCLC Meta‑analyses Collaborative Group. Lancet.
2014;383:1561‑1571.9. Pardoll DM. Nat Rev Cancer. 2012;12:252–264.10. Brahmer JR, et al. J Clin Oncol. 2010;28:3167–3175.
11. Topalian SL, et al. N Engl J Med. 2012;366:2443–2454.
12. Wang C, et al. Cancer Immunol Res. 2014;2:846–856.
13. OPDIVO® (nivolumab) [package insert]. Princeton, NJ: Bristol‑Myers Squibb Company; March 2020.
14. OPDIVO® [summary of product characteristics]. Uxbridge, UK: Bristol‑Myers Squibb Company; March 2020.
15. Bracci L, et al. Cell Death Differ. 2014;21:15−25.
16. Roselli M, et al. Oncoimmunology. 2013;2:e27025.
17. Reuss JE, et al. Poster presentation at the ASCO Annual Meeting; May 31‑June 4, 2019; Chicago IL. Abstract# 8524.
18. Cascone T, et al. Oral presentation at the ASCO Annual Meeting; May 31‑June 4, 2019; Chicago IL. Abstract# 8504.
19. Provencio M, et al. Oral presentation at the World Conference on Lung Cancer; September 7‑10; Barcelona, Spain. Abstract# OA13.05.
Acknowledgments• The patients and families for making this trial
possible• The contributions of the study teams from the
sites involved in the trial• The protocol manager for this study, Jonathan
Steuve
• Bristol Myers Squibb (Princeton, NJ) and ONO Pharmaceutical Company Ltd. (Osaka, Japan)
• The study was supported by Bristol Myers Squibb• All authors contributed to and approved the
presentation; writing assistance was provided by Scarlett Geunes‑Boyer, PhD, of Bio Connections, funded by Bristol Myers Squibb
To request a copy of this poster:
Scan QR codevia a barcode
reader application
QR codes are valid for 30 days after the congress presentation date.
Scientific Content on Demand
