How Pembrolizumab Works for Lung Cancer — and Who Qualifies Based on PD-L1 Testing

Research-informed explainer — last updated April 12, 2026

Pembrolizumab (Keytruda) can replace chemotherapy entirely as first-line treatment for patients with non-small-cell lung cancer whose tumors express PD-L1 in at least 50% of cells. For patients with lower PD-L1 expression, combining pembrolizumab with chemotherapy has also improved survival compared with chemotherapy alone — but a simple biomarker test now determines which approach applies to you.

The evidence for this shift in treatment comes from researchers at leading cancer centers. Julie Brahmer, Professor of Oncology at Johns Hopkins and Director of the Thoracic Oncology Program, is the senior author on KEYNOTE-024, the landmark trial comparing pembrolizumab to chemotherapy in PD-L1-high lung cancer (9,913 citations), and the first author of the foundational phase I trial establishing anti-PD-L1 antibody safety and activity across cancers (7,942 citations). Neal Ready, Professor of Medicine at Duke University School of Medicine, contributed to the CheckMate 017 and 057 trials showing nivolumab outperformed docetaxel in both squamous and nonsquamous NSCLC after chemotherapy failure (9,393 and 8,491 citations respectively). Bruce Johnson, Professor Emeritus at Harvard Medical School and Institute Physician at Dana-Farber Cancer Institute, published on molecular profiling of BRAF-mutant NSCLC to clarify which patients are candidates for targeted therapy rather than immunotherapy. Jennifer Temel, Clinical Director of Thoracic Oncology at Massachusetts General Hospital, led the landmark NEJM trial demonstrating that early palliative care alongside lung cancer treatment improves both survival and quality of life (7,315 citations).

How the PD-1 checkpoint works — and how pembrolizumab disrupts it

Your immune system normally uses checkpoint proteins to avoid attacking healthy tissue. One of these checkpoints is the PD-1 receptor on T cells. When PD-1 binds to PD-L1 — a protein displayed on some tumor cells — it sends a "stand down" signal that prevents T cells from killing the cancer.

Pembrolizumab is a monoclonal antibody that blocks PD-1, keeping that "stand down" signal from being sent. When the brake is released, T cells can recognize and attack tumor cells. The 2012 New England Journal of Medicine trial by Brahmer and colleagues first demonstrated this mechanism working in humans across multiple cancer types, with durable responses even at that early stage of investigation (12,532 citations for the anti-PD-1 safety and activity trial).

The critical discovery was that tumors with higher PD-L1 expression — meaning more of the "stand down" signal being displayed — tend to respond better to checkpoint blockade. This led directly to the development of the PD-L1 test.

What PD-L1 testing involves and what the results mean

Before starting pembrolizumab, your oncologist will order a PD-L1 immunohistochemistry (IHC) test on tumor tissue. The test measures the tumor proportion score (TPS) — the percentage of tumor cells staining positive for PD-L1.

PD-L1 scores and treatment implications:

The KEYNOTE-024 trial, with Brahmer as senior author, enrolled patients with TPS of 50% or higher and found pembrolizumab produced a progression-free survival of 10.3 months versus 6 months with platinum-based chemotherapy. More importantly, pembrolizumab was associated with significantly better overall survival and fewer severe side effects.

Molecular testing must come first: EGFR, ALK, BRAF, and other drivers

Not every lung cancer patient is a candidate for first-line immunotherapy, even if their PD-L1 score is high. Several driver mutations — particularly EGFR mutations, ALK rearrangements, and BRAF V600E mutations — define tumors that respond to targeted therapies more reliably than to checkpoint inhibitors.

Bruce Johnson's work on BRAF V600E-mutant NSCLC illustrates why this matters. His 2017 Lancet Oncology trial of dabrafenib plus trametinib in previously untreated BRAF V600E-mutant NSCLC showed a 64% objective response rate — performance that checkpoint inhibitors rarely match in this genomic subset. Guidelines from major cancer organizations require testing for EGFR, ALK, ROS1, BRAF, KRAS, MET, RET, and NTRK before recommending immunotherapy as first-line treatment.

This means the workup for a newly diagnosed lung cancer patient involves more than one test. Your oncologist will order comprehensive molecular profiling (often via next-generation sequencing of the tumor) alongside PD-L1 testing before finalizing a treatment plan.

Second-line immunotherapy: what happens after chemotherapy fails

Neal Ready's work on the CheckMate trials helped establish the standard of care for patients who had already received chemotherapy. In the CheckMate 017 trial (squamous-cell NSCLC) and CheckMate 057 (nonsquamous NSCLC), nivolumab — another PD-1 inhibitor — produced better overall survival and a more favorable side effect profile than docetaxel in patients whose disease had progressed after first-line platinum-based chemotherapy. These trials enrolled patients regardless of PD-L1 status, which is why PD-1 inhibitors are a standard second-line option even for patients with low or negative PD-L1 expression.

The practical implication: if you received chemotherapy first and did not have prior biomarker testing, a PD-1 inhibitor is likely a valid next step. If your cancer was diagnosed recently and profiled upfront, pembrolizumab-based therapy may have already been incorporated into your initial treatment plan.

Side effects: what distinguishes immunotherapy from chemotherapy

Pembrolizumab does not cause the same side effects as cytotoxic chemotherapy. Hair loss, severe nausea, and bone marrow suppression are uncommon. Instead, the risks are inflammation-related and stem from the immune system being broadly activated.

Common immune-related adverse events include:

• Fatigue and flu-like symptoms (most common, usually manageable)
• Skin rash or itching
• Hypothyroidism (requires thyroid hormone replacement but is generally well controlled)
• Colitis (inflammation of the colon) — presents as severe diarrhea
• Pneumonitis (lung inflammation) — a serious side effect requiring prompt evaluation
• Hepatitis (liver inflammation) — detected on routine blood work

Severe immune-related adverse events occur in roughly 10–15% of patients receiving pembrolizumab alone, and at higher rates in combination regimens. Most are managed by pausing the drug and giving corticosteroids. Rarely, immune-related adverse events can be life-threatening.

Palliative care is not giving up — it is part of the treatment plan

Jennifer Temel's 2010 NEJM trial enrolled 151 patients with newly diagnosed metastatic NSCLC and randomly assigned them to standard oncology care alone or standard care plus early palliative care consultations. The palliative care group had better quality of life, less depression, received less aggressive care at end of life — and lived a median of 11.6 months versus 8.9 months. The survival benefit, not the quality-of-life benefit, surprised the oncology community.

The lesson for patients: asking for palliative care early does not mean you are giving up on treatment. The American Society of Clinical Oncology, in guidelines co-authored by Temel, now recommends that all patients with advanced NSCLC receive integrated palliative care alongside standard oncology treatment.

Questions to ask your doctor

• What is my PD-L1 tumor proportion score, and has my tumor been tested for EGFR, ALK, BRAF, and other driver mutations?
• Am I a candidate for pembrolizumab alone, or does my situation call for combination with chemotherapy?
• If my PD-L1 score is negative, what immunotherapy options might still apply to me?
• What immune-related side effects should I watch for, and when should I call the office versus go to the emergency room?
• How does pembrolizumab fit into my overall treatment plan, and is palliative care support available to me now?

The bottom line

Pembrolizumab has changed the standard of care for non-small-cell lung cancer by offering a chemotherapy-free option for patients with PD-L1 expression of 50% or higher and no actionable driver mutations. The selection process requires molecular profiling of the tumor first — PD-L1 testing alone is not sufficient. If you have been newly diagnosed with advanced NSCLC, ask your oncologist whether comprehensive biomarker testing has been completed before a treatment plan is finalized.