CheckMate 649: Additional Analysis From the

Phase III Trial of First-line Nivolumab + CT vs

CT for Advanced Gastroesophageal Cancers
CCO Independent Conference Highlights*
of the 2021 Virtual ASCO Annual Meeting, June 4-8, 2021

*CCO is an independent medical education company that provides state-of-the-art medical information to
healthcare professionals through conference coverage and other educational programs.

Provided by Clinical Care Options, LLC

Supported by an educational grant from Merck Sharp & Dohme Corp.

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 CheckMate 649: Background
 Prognosis for patients with advanced or metastatic HER2-negative
GC/GEJC receiving first-line CT is poor1-4
 CheckMate 649 compared first-line nivolumab + CT with CT alone in
patients with advanced GC/GEJC/EAC5
‒ Based on data from initial analysis, nivolumab + CT approved by FDA for
use in this setting
 Current analysis reports additional efficacy, safety data from CheckMate
6496,7

1. Lordick. Lancet Oncol. 2013;14:490. 2. Catenacci. Lancet Oncol. 2017;18:1467. 3. Shah. JAMA Oncol. 2017;3:620. 4. Fuchs. Lancet Oncol.
2019;20:420. 5. Moehler. ESMO 2020. Abstr LBA6. 6. Moehler. ASCO 2021. Abstr 4002. 7. Janjigian. Lancet. 2021;[Epub]. Slide credit: clinicaloptions.com
CheckMate 649: Study Design
 International, randomized, open-label phase III trial
Stratified by PD-L1 (≥1% vs <1%), region (Asia vs US/Canada vs rest
of world), ECOG PS (0 vs 1), CT (XELOX vs FOLFOX)
Current analysis

Nivolumab 360 mg + XELOX Q3W or

Until PD
Nivolumab 240 mg + FOLFOX Q2W
Patients with previously (treatment
(n = 789)
untreated, unresectable beyond PD
advanced or metastatic gastric XELOX Q3W or permitted for
cancer, GEJ, or esophageal FOLFOX Q2W nivolumab + CT),
adenocarcinoma; not known to (n = 792) unacceptable
be HER2 positive; ECOG PS 0/1 toxicity, consent
(N = 1581) Nivolumab + Ipilimumab Q3W x 4 followed by withdrawal, or
Nivolumab 240 mg Q2W end of study

 Coprimary endpoints: OS and PFS in patients with PD-L1 CPS ≥5

 Secondary endpoints: OS and PFS in all randomized patients and patients with
PD-L1 CPS ≥10 and ≥ 1, BICR-assessed ORR
Slide credit: clinicaloptions.com
 CheckMate 649: Baseline Characteristics

Characteristic Nivolumab + CT CT Characteristic Nivolumab + CT CT

(n = 789) (n = 792) (n = 789) (n = 792)
Median age, yr 62 (18-88) 61 (21-90) Metastatic 96 95
(range) disease, %
Male, % 68 71 Liver
38 40
metastases, %
Race, %
 Asian 24 24 Signet ring cell
18 17
 Non-Asian 76 76 carcinoma, %
ECOG PS 1, % 59 57 MSI status,* %
 MSS 88 86
Primary tumor  MSI-H 3 3
location, %
 GC 70 70 FOLFOX/XELOX
 GEJC 17 16 received on 54/46 53/47
 EAC 13 14 study,† %
*For 71 patients In the nivolumab + CT and 89 patients in the CT group, the MSI status was invalid/not available.
†
Includes patients who received at least 1 dose of FOLFOX/XELOX (nivolumab + CT, n = 782; CT, n = 767)
Moehler. ASCO 2021. Abstr 4002. Janjigian. Lancet. 2021;[Epub]. Slide credit: clinicaloptions.com
 CheckMate 649: Overall OS and PFS
Nivo + CT CT Nivo + CT CT
(n = 789) (n = 792) (n = 789) (n = 792)
Median OS, months (95% CI) 13.8 (12.6-14.6) 11.6 (10.9-12.5) Median PFS, months (95% CI) 7.7 (7.1-8.5) 6.9 (6.6-7.1)
100 HR 0.80 (99.3% CI 0.68-0.94); P = .0002 100 HR 0.77 (95% CI 0.68-0.87)
Overall Survival (%)

Progression-Free
80 80

Survival (%)
60 60
40 40

20 20

0 0
0 3 6 9 12 15 18 21 24 27 30 33 36 39 0 3 6 9 12 15 18 21 24 27 30 33 36
Number at Risk
Time Since Randomization (months) Time Since Randomization (months)
(Number Censored)
Nivolumab plus 789 731 621 506 420 308 226 147 100 49 34 14 2 0 789 639 429 287 197 136 83 51 31 15 11 1 0
chemotherapy (0) (4) (13) (16) (20) (63) (90) (167) (167) (201) (212) (231) (243) (245) (0) (38) (84) (105) (125) (149) (173) (193) (207) (217) (220) (229) (230)
Chemotherapy 792 607 586 469 359 239 160 94 59 35 15 7 2 0 792 544 351 202 120 65 38 28 18 12 6 1 0
alone (0) (17) (22) (29) (34) (68) (94) (136) (157) (172) (187) (194) (199) (201) (0) (92) (133) (155) (173) (199) (211) (216) (222) (225) (229) (234) (235)

 Minimum follow-up: 12.1 mo

 Nivolumab + CT increased OS vs CT in most prespecified subgroups
Janjigian. Lancet. 2021;[Epub]. Slide credit: clinicaloptions.com
 CheckMate 649: Overall Response

Outcome Nivolumab + CT CT
(n = 603) (n = 608)
ORR, % (95% CI) 58 (54-62) 46 (42-50)

Best overall response, %

 CR 10 6
 PR 48 40
 SD 28 33
 PD 7 10
 NE 7 11

Median TTR, mo (range) 1.5 (0.8-10.9) 1.5 (0.6-7.1)

Median DoR, mo (95% CI) 8.5 (7.2-9.9) 6.9 (5.8-7.2)

Moehler. ASCO 2021. Abstr 4002. Janjigian. Lancet. 2021;[Epub]. Slide credit: clinicaloptions.com
 CheckMate 649: Subgroup Analysis by PD-L1 CPS
Median, Mo ORR, %
Unstratified Unweighted
PD-L1 CPS* n Nivolumab PD-L1 n Difference in
CT HR† CPS‡ Nivolumab
+ CT + CT CT ORR, %
OS (overall) 1581 13.8 11.6 0.79
 <1 265 13.1 12.5 0.92 Overall 1211 58 46 12
 ≥1 1296 14.0 11.3 0.76  <1 178 51 41 9
 <5 606 12.4 12.3 0.94  ≥1 1019 60 46 13
 ≥5 955 14.4 11.1 0.70  <5 428 55 46 9
 ≥5 769 60 45 15
PFS (overall) 1581 7.7 6.9 0.77
 <1 265 8.7 8.1 0.93
 ≥1 1296 7.5 6.9 0.75 *PD-L1 CPS expression was intermediate, unevaluable, or unavailable
 <5 606 7.5 8.2 0.93 for 20 patients. †Unstratified HR for death or progression to death
 ≥5 955 7.7 6.1 0.69 ‡
Randomized patients with target lesion at baseline. PD-L1 CPS
expression was intermediate, unevaluable, or unavailable for 14
patients.

 Survival benefit with nivolumab + CT was enriched at higher PD-L1 CPS cutoffs
 ORR benefit of nivolumab + CT vs CT was consistent across all assessed subgroups
Moehler. ASCO 2021. Abstr 4002. Janjigian. Lancet. 2021;[Epub]. Slide credit: clinicaloptions.com
 CheckMate 649: TRAEs With Potential Immunologic
Cause in Patients Treated With Nivolumab + CT
Nivolumab + CT (n = 782)
Select TRAEs
Any Grade, n (%) Grade 3/4, n (%)

Endocrine 107 (14) 5 (<1)

Gastrointestinal 262 (34) 43 (5)
Hepatic 203 (26) 29 (4)
Pulmonary 40 (5) 14 (2)
Renal 26 (3) 6 (<1)
Skin 214 (27) 26 (3)

Moehler. ASCO 2021. Abstr 4002. Janjigian. Lancet. 2021;[Epub]. Slide credit: clinicaloptions.com
 CheckMate 649: Onset and Resolution of TRAEs With
Potential Immunologic Cause With Nivolumab + CT
Nivolumab + CT (n = 782)

Select TRAEs Median Time to

Median Time to Resolution, Wk Resolved, n/N (%) Patients Receiving
Onset, Wk (Range) IMM,* n (%)
(Range)

Endocrine 15.0 (2.0-124.3) 72.1 (0.4-139.1) 46/107 (43) 13 (12)

Gastrointestinal 4.3 (0.1-93.6) 1.6 (0.1-117.6) 228/161 (87) 28 (11)
Hepatic 7.9 (0.1-61.3) 10.1 (0.4-150.6) 156/200 (78) 23 (11)
Pulmonary 23.9 (1.6-96.9) 10.1 (0.3-121.3) 28/40 (70) 31 (78)
Renal 12.4 (1.7-59.4) 3.1 (0.1-42.4) 19/26 (73) 6 (23)
Skin 9.6 (0.1-97.4) 23.4 (0.1-153.6) 124/214 (58) 84 (39)
*Includes corticosteroids.

Moehler. ASCO 2021. Abstr 4002. Janjigian. Lancet. 2021;[Epub]. Slide credit: clinicaloptions.com
 CheckMate 649: Time to Symptom Deterioration and
Patient QoL
Nivolumab Chemotherapy
+ Chemotherapy Alone
100 (n = 789) (n = 792)

No Deterioration (%)*
Median, months (95% CI) NR (22.6-NE) 21.0 (12.5-NE)
80
HR 0.77 (95% CI 0.63-0.95); P = .0129
60
40

20

0
0 3 6 9 12 15 18 21 24 27 30 33 36
Number at Risk Time Since Randomization (months)
Nivolumab plus chemotherapy 789 478 303 198 143 96 57 38 9 6 4 1 0
Chemotherapy alone 792 367 211 117 63 33 19 12 5 5 2 1 0
 Most patients in both treatment arms reported being “not at all” or “a little” bothered by treatment adverse events
(FACT-Ga GP5 questionnaire)

 Adding nivolumab to CT did not cause patients to be more bothered by treatment adverse events
Moehler. ASCO 2021. Abstr 4002. Janjigian. Lancet. 2021;[Epub]. Slide credit: clinicaloptions.com
 CheckMate 649: Conclusions
 In the phase III CheckMate 649 trial in untreated patients with advanced
gastroesophageal cancers, nivolumab + CT significantly prolonged OS and PFS
in all treated patients and in patients with PD-L1 CPS ≥5
‒ Median OS, all treated patients: 13.8 vs 11.6 mo (HR: 0.80; P = .0002);
median PFS: 7.7 vs 6.9 mo (HR: 0.77)
 Treatment-related AEs with potential immunologic cause occurred in
≤5% per site at grade 3/4 severity; most cases resolved with standard
management
 Investigators concluded that data support nivolumab + CT as standard
first-line treatment for patients with advanced non-HER2+ gastroesophageal
cancers
Moehler. ASCO 2021. Abstr 4002. Janjigian. Lancet. 2021;[Epub]. Slide credit: clinicaloptions.com
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