The New England Journal of Medicine SEPTEMBER 06, 2018

Pembrolizumab plus Chemotherapy for Squamous Non–Small-Cell Lung Cancer (KEYNOTE-407)

Luis Paz-Ares, et al.

Bottom Line

The KEYNOTE-407 phase III trial demonstrated that the addition of pembrolizumab to platinum-based chemotherapy significantly improves overall survival and progression-free survival in patients with metastatic squamous non-small-cell lung cancer, establishing a new standard of care regardless of PD-L1 expression.

Key Findings

1. The addition of pembrolizumab to chemotherapy significantly improved overall survival, with a hazard ratio of 0.71 (95% CI, 0.59 to 0.85) at a median follow-up of 56.9 months.

2. The 5-year overall survival rate was substantially higher in the pembrolizumab plus chemotherapy arm compared to the placebo plus chemotherapy arm (18.4% vs 9.7%).

3. Progression-free survival was also significantly improved, with a hazard ratio of 0.62 (95% CI, 0.52 to 0.74).

4. The survival benefit was observed consistently regardless of the tumor's PD-L1 expression level (TPS <1% or ≥1%).

5. Among patients who completed the full 35 cycles of pembrolizumab, the 5-year survival rate reached 69.5%, indicating a subset of patients achieves durable, long-term benefit.

Study Design

Design

RCT

Double-Blind

Sample

559

Patients

Duration

56.9 mo

Median

Setting

Multicenter, global

Population Treatment-naïve patients with metastatic squamous non-small-cell lung cancer (NSCLC)

Intervention Pembrolizumab (200 mg) every 3 weeks for up to 35 cycles plus platinum-based chemotherapy (carboplatin and either paclitaxel or nab-paclitaxel) for 4 cycles

Comparator Placebo plus platinum-based chemotherapy (carboplatin and either paclitaxel or nab-paclitaxel) for 4 cycles

Outcome Overall survival and progression-free survival assessed by blinded independent central review (BICR)

Study Limitations

• The study allowed for crossover of patients from the placebo arm to anti-PD-(L)1 therapy upon disease progression, which potentially confounds the overall survival analysis.

• The long-term 5-year analysis is exploratory in nature, performed after the primary protocol-specified endpoints were matured.

• Higher rates of treatment discontinuation and specific adverse events, such as immune-related toxicities, were observed in the experimental arm compared to chemotherapy alone.

• There was a limited number of patients remaining at risk at the 5-year landmark, which requires caution in interpreting the absolute survival rate estimates.

Clinical Significance

KEYNOTE-407 solidified the role of immune checkpoint inhibitors in the first-line setting for squamous NSCLC, a traditionally difficult-to-treat subtype. By demonstrating clear efficacy improvements irrespective of PD-L1 status, it broadened the therapeutic options for patients, although clinicians must carefully manage the unique toxicity profile associated with the chemo-immunotherapy combination.

Historical Context

Prior to the results of KEYNOTE-407, standard first-line treatment for metastatic squamous NSCLC was limited to platinum-based chemotherapy doublets, which historically yielded poor long-term outcomes with 5-year survival rates typically under 10%. The trial followed the successful demonstration of pembrolizumab-chemotherapy efficacy in non-squamous NSCLC (KEYNOTE-189), providing a parallel, definitive validation for the squamous histology.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How does the mechanism of action of pembrolizumab as a PD-1 inhibitor facilitate an anti-tumor immune response, and why might combining it with cytotoxic chemotherapy be theoretically synergistic in squamous NSCLC?

Key Response

Pembrolizumab blocks the PD-1 receptor on T-cells, preventing the interaction with PD-L1 on tumor cells that normally 'turns off' the T-cell. Chemotherapy can kill tumor cells and cause 'immunogenic cell death,' which releases tumor-specific antigens and pro-inflammatory signals that can further prime and activate the T-cells now liberated by the checkpoint inhibitor.

Resident

In a patient with metastatic squamous NSCLC and a PD-L1 Tumor Proportion Score (TPS) of 0%, how do the KEYNOTE-407 results influence your first-line treatment recommendation compared to a chemotherapy-only approach?

Key Response

The KEYNOTE-407 trial demonstrated a significant improvement in overall survival (OS) and progression-free survival (PFS) across all PD-L1 expression levels, including the <1% group. Therefore, the addition of pembrolizumab to a platinum-doublet is recommended as a standard of care regardless of PD-L1 status, unless contraindications to immunotherapy exist.

Fellow

For a patient with high PD-L1 expression (TPS ≥50%) and squamous histology, when might you still prefer the KEYNOTE-407 triplet regimen (Pembrolizumab + Chemo) over Pembrolizumab monotherapy (KEYNOTE-024)?

Key Response

While monotherapy is an option for TPS ≥50%, the combination regimen (KEYNOTE-407) is often preferred for patients with a high tumor burden, symptomatic disease, or aggressive progression where a rapid objective response is needed, as chemotherapy-immunotherapy combinations typically offer higher objective response rates (ORR) than immunotherapy alone.

Attending

Historically, squamous NSCLC has had a poorer prognosis and fewer targeted therapy options than adenocarcinoma. How does the magnitude of the survival benefit seen in KEYNOTE-407 redefine the 'ceiling' of clinical expectations for this specific histology?

Key Response

Prior to this trial, squamous NSCLC lacked the oncogenic drivers (EGFR/ALK) that permitted targeted therapy in non-squamous types. KEYNOTE-407 established that immunotherapy efficacy is histology-agnostic in the first line, effectively doubling the median survival in many cohorts and shifting the standard of care from palliative chemotherapy to an 'immunotherapy-backbone' approach for nearly all patients.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The KEYNOTE-407 trial allowed for crossover from the placebo-combination group to pembrolizumab upon disease progression. Critically evaluate how this crossover affects the Hazard Ratio (HR) for Overall Survival and which statistical models are best suited to address this potential dilution of effect?

Key Response

Crossover can lead to an underestimate of the true treatment effect on OS (bringing the HR closer to 1.0). To address this, investigators often employ Rank-Preserving Structural Failure Time (RPSFT) models or inverse probability of censoring weighting (IPCW) to estimate survival outcomes as if the control arm had never received the experimental agent, often revealing a more pronounced survival benefit.

Journal Editor

The trial utilized a chemotherapy backbone of carboplatin plus either paclitaxel or nab-paclitaxel. As a reviewer, how would you evaluate the external validity of these results for regions or institutions where cisplatin is the preferred platinum agent for 'fit' patients with squamous histology?

Key Response

A critical reviewer would flag that while carboplatin is more widely tolerated, cisplatin is sometimes considered more efficacious in certain squamous contexts. However, most modern oncology standards view carboplatin/paclitaxel as a globally accepted surrogate, and the overwhelming survival benefit of the pembrolizumab addition suggests the 'immunotherapy effect' likely transcends the specific platinum salt used.

Guideline Committee

The NCCN and ASCO guidelines now list Pembrolizumab + Carboplatin + (nab-)Paclitaxel as a Category 1 recommendation for first-line squamous NSCLC. Does the KEYNOTE-407 data support this recommendation for patients with a performance status (PS) of 2 or higher, and how should guidelines address this population?

Key Response

KEYNOTE-407 predominantly enrolled patients with an ECOG PS of 0 or 1. While guidelines list this as a Category 1 recommendation, they usually include a caveat that evidence for PS ≥2 is limited. Future updates should emphasize that while the regimen is standard for fit patients, dose modifications or monotherapy might be more appropriate for PS 2 patients, as they are at higher risk for toxicity and were underrepresented in the pivotal trial.

Clinical Landscape

Noteworthy Related Trials

2018

KEYNOTE-189

n = 616 · NEJM

Tested

Pembrolizumab plus pemetrexed and platinum-based chemotherapy

Population

Patients with previously untreated metastatic nonsquamous NSCLC without EGFR or ALK mutations

Comparator

Placebo plus pemetrexed and platinum-based chemotherapy

Endpoint

Overall survival and progression-free survival

Key result: The addition of pembrolizumab to chemotherapy resulted in significantly longer overall survival and progression-free survival compared to chemotherapy alone.

2018

IMpower131

n = 1021 · Lancet Oncol

Tested

Atezolizumab plus carboplatin and nab-paclitaxel

Population

Patients with stage IV squamous NSCLC

Comparator

Carboplatin and nab-paclitaxel

Endpoint

Progression-free survival and overall survival

Key result: The addition of atezolizumab to chemotherapy significantly improved progression-free survival in patients with squamous NSCLC, particularly those with high PD-L1 expression.

2019

KEYNOTE-042

n = 1274 · Lancet

Tested

Pembrolizumab monotherapy

Population

Patients with locally advanced or metastatic NSCLC with PD-L1 TPS of 1% or greater

Comparator

Platinum-based chemotherapy

Endpoint

Overall survival

Key result: Pembrolizumab monotherapy significantly improved overall survival compared with chemotherapy in patients with PD-L1 expression of 1% or more.

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