The Lancet JULY 03, 2021

First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial

Janjigian YY, Shitara K, Moehler M, et al.

Bottom Line

In patients with previously untreated, HER2-negative advanced gastroesophageal adenocarcinoma, the addition of nivolumab to standard chemotherapy significantly improved overall survival and progression-free survival, particularly in those with PD-L1 expression (CPS ≥5).

Key Findings

1. In the primary analysis population (PD-L1 CPS ≥5), nivolumab plus chemotherapy demonstrated a statistically significant improvement in overall survival compared to chemotherapy alone (median OS 13.8 months vs 11.6 months; hazard ratio 0.71, P<0.0001).

2. Progression-free survival was also significantly improved in the PD-L1 CPS ≥5 population (median PFS 7.7 months vs 6.0 months; hazard ratio 0.68, P<0.0001).

3. Long-term 5-year follow-up results indicated a sustained survival benefit in the PD-L1 CPS ≥5 subgroup, with a 5-year OS rate of 16% in the nivolumab plus chemotherapy arm compared to 6% in the chemotherapy arm.

4. The clinical benefit was maintained across the broader patient population (regardless of PD-L1 expression), supporting its broad application as a standard first-line therapy.

5. Grade 3 or 4 treatment-related adverse events occurred in 60% of patients receiving the combination compared to 45% in the chemotherapy-only group, reflecting the expected toxicity profile of adding immune checkpoint inhibition to cytotoxic agents.

Study Design

Design

RCT

Open-Label

Sample

1,581

Patients

Duration

60.1 mo

Median

Setting

Multicenter, global

Population Adults with previously untreated, unresectable, HER2-negative, advanced or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma.

Intervention Nivolumab (360 mg q3w or 240 mg q2w) plus chemotherapy (CapeOX or FOLFOX).

Comparator Chemotherapy alone (CapeOX or FOLFOX).

Outcome Overall survival and progression-free survival in patients with PD-L1 CPS ≥5.

Study Limitations

• The trial was open-label, which may introduce observer bias in the assessment of progression-free survival.

• The benefit of nivolumab appeared most pronounced in patients with higher PD-L1 expression (CPS ≥5), necessitating careful patient selection in clinical practice.

• The chemotherapy backbone varied (XELOX or FOLFOX), and potential differences in the interaction between these regimens and nivolumab were not the primary focus of the study's power analysis.

• The study excluded HER2-positive patients, limiting the generalizability of these findings to that specific molecular subtype.

Clinical Significance

CheckMate 649 established the combination of nivolumab and chemotherapy as a new global standard of care for first-line treatment of advanced, HER2-negative gastroesophageal adenocarcinoma, providing a durable survival advantage previously unattainable with chemotherapy alone.

Historical Context

Prior to this trial, the standard of care for advanced HER2-negative gastroesophageal cancer relied on platinum/fluoropyrimidine-based chemotherapy, which typically yielded a median overall survival of less than one year. CheckMate 649 provided the pivotal evidence required to integrate immune checkpoint inhibitors into the frontline setting for these aggressive malignancies.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the biological rationale for combining a PD-1 inhibitor like nivolumab with cytotoxic chemotherapy, and how does the PD-L1 Combined Positive Score (CPS) differ from the Tumor Proportion Score (TPS) used in other cancers?

Key Response

Chemotherapy can induce immunogenic cell death, releasing tumor antigens that may enhance the efficacy of PD-1 inhibitors which work by 'releasing the brakes' on T-cells. Unlike TPS, which only measures PD-L1 expression on tumor cells, CPS includes tumor cells, lymphocytes, and macrophages, providing a more comprehensive assessment of the immune microenvironment in gastrointestinal malignancies.

Resident

In a patient with newly diagnosed HER2-negative metastatic gastric adenocarcinoma, how should the CheckMate 649 results influence your initial management plan if the patient's PD-L1 CPS is found to be less than 1?

Key Response

While the FDA approved the nivolumab-chemotherapy combination for all-comers, CheckMate 649 showed that the survival benefit is highly dependent on PD-L1 expression. In the CPS <1 subgroup, the hazard ratio for overall survival often crosses 1.0, suggesting minimal to no benefit. Therefore, a resident should recognize that while legal to prescribe, the clinical value of adding immunotherapy is questionable in PD-L1 negative patients compared to those with CPS ≥5.

Fellow

How does the presence of Microsatellite Instability-High (MSI-H) status confound the interpretation of the overall survival benefit observed in the CheckMate 649 intent-to-treat population, particularly regarding the CPS 1–5 subgroup?

Key Response

MSI-H patients (approx. 3-5% of the cohort) derive an outsized benefit from immunotherapy. Post-hoc analyses of CheckMate 649 suggest that when MSI-H patients are excluded, the survival benefit in the CPS 1–5 and CPS <1 populations is significantly diminished or lost. A fellow must distinguish whether the 'all-comer' benefit is driven by a small hyper-responsive MSI-H group or a broad effect across MSS patients.

Attending

Considering the standard of care shift established by CheckMate 649, how do you balance the survival advantage against the increased risk of Grade 3/4 immune-related adverse events (irAEs) in a population often presenting with significant nutritional deficiencies and poor performance status?

Key Response

The trial reported Grade 3-4 treatment-related adverse events in 59% of the combination arm vs 44% in the chemo-alone arm. In clinical practice, the 'real-world' patient often has more comorbidities than trial participants. Attending-level judgment involves assessing if the ~3-month median OS improvement justifies the potential for life-altering toxicities like colitis or pneumonitis in a fragile gastric cancer patient.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

Analyze the hierarchical testing strategy employed in CheckMate 649; how does this statistical design impact the validity of conclusions drawn for the PD-L1 CPS <5 subgroup?

Key Response

The trial used a hierarchical gatekeeping procedure (testing CPS ≥5 first, then CPS ≥1, then all randomized). While this controls the family-wise Type I error rate, it allows a trial to claim a 'positive' result for the total population even if the benefit is entirely driven by the high-expression subgroup. A researcher must look at the forest plots and interaction tests to determine if there is truly a treatment effect in the lower-expression strata.

Journal Editor

Given that CheckMate 649 was an open-label trial, what specific threats to internal validity would you flag regarding the Progression-Free Survival (PFS) endpoint and the rate of subsequent therapies in the control arm?

Key Response

Open-label designs can introduce investigator bias in determining disease progression. While Blinded Independent Central Review (BICR) helps, the knowledge of treatment assignment can also influence the choice of second-line therapies. If the control arm patients were significantly less likely to receive subsequent immunotherapy (which they were in many regions), the OS benefit might be an artifact of lack of access to effective later-line agents rather than the superiority of frontline combination.

Guideline Committee

How do the CheckMate 649 results reconcile with the varying recommendations between NCCN and ESMO guidelines regarding the PD-L1 CPS threshold for the use of first-line nivolumab?

Key Response

NCCN guidelines (v1.2024) provide a Category 1 recommendation for nivolumab + chemo in patients with CPS ≥5 but a lower Category 2B recommendation for CPS 1-4. In contrast, ESMO guidelines are stricter, generally recommending the addition of nivolumab only for those with CPS ≥5. The committee must decide if the modest benefit in low-expressors justifies the high cost-benefit ratio and potential for toxicity, often leading to divergent international 'strengths of recommendation'.

Clinical Landscape

Noteworthy Related Trials

2010

ToGA Trial

n = 594 · Lancet

Tested

Trastuzumab plus chemotherapy

Population

Patients with HER2-positive advanced gastric or gastro-oesophageal junction cancer

Comparator

Chemotherapy alone

Endpoint

Overall survival

Key result: The addition of trastuzumab to chemotherapy significantly improved overall survival compared to chemotherapy alone in HER2-positive patients.

2021

KEYNOTE-062

n = 763 · Lancet

Tested

Pembrolizumab monotherapy or pembrolizumab plus chemotherapy

Population

Patients with advanced gastric or gastro-oesophageal junction adenocarcinoma with PD-L1 CPS ≥1

Comparator

Chemotherapy plus placebo

Endpoint

Overall survival and progression-free survival

Key result: Pembrolizumab did not demonstrate superiority over chemotherapy for overall survival in patients with PD-L1 CPS ≥1 or ≥10.

2021

ATTRACTION-4

n = 724 · Lancet Oncol

Tested

Nivolumab plus chemotherapy

Population

Patients with previously untreated unresectable advanced or recurrent HER2-negative gastric or gastro-oesophageal junction cancer

Comparator

Chemotherapy plus placebo

Endpoint

Progression-free survival

Key result: Nivolumab plus chemotherapy significantly improved progression-free survival compared to chemotherapy alone in the Asian population.

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