Keytruda (Pembrolizumab): 25 Landmark KEYNOTE Trials That Changed Cancer Treatment (2026)

Keytruda (pembrolizumab) is one of the most consequential cancer medicines of the modern immunotherapy era. Its development transformed the role of PD-1 blockade from an experimental strategy for advanced melanoma into a treatment platform spanning multiple tumor types, biomarkers, disease stages and treatment settings.

This review examines 25 landmark KEYNOTE trials and explains what each contributed to oncology: proof of concept, biomarker selection, combination therapy, tumor-agnostic treatment, perioperative therapy, adjuvant treatment, and long-term disease control.

Evidence status: Phase 3 randomized trials are emphasized. Results are interpreted according to their original trial populations and should not be generalized to cancers or biomarker groups that were not studied.

Bottom line: The KEYNOTE program did more than establish another anticancer drug. It helped establish a new therapeutic model: identify an immune-sensitive tumor, release PD-1-mediated inhibition, combine immunotherapy when appropriate, and increasingly intervene before metastatic disease becomes established.

Contents

1. What is Keytruda?
2. The KEYNOTE revolution: a clinical timeline
3. 25 landmark KEYNOTE trials
4. Detailed trial analysis
5. The biomarker revolution
6. From metastatic disease to curative-intent treatment
7. Why Keytruda combinations became important
8. Long-term responders and survival
9. What the KEYNOTE trials do not prove
10. How to interpret a KEYNOTE trial
11. Conclusion
12. Selected references

1. What Is Keytruda?

Keytruda is the brand name for pembrolizumab, a monoclonal antibody targeting the programmed cell death protein 1 (PD-1) immune checkpoint.

PD-1 is an inhibitory receptor expressed on activated T cells. Tumors can exploit the PD-1/PD-L1 pathway to suppress antitumor immune activity. Pembrolizumab blocks PD-1 signaling, potentially restoring T-cell activity against tumor cells.

The therapeutic concept is fundamentally different from conventional cytotoxic chemotherapy. Chemotherapy directly damages rapidly dividing cells, whereas immune checkpoint blockade attempts to modify the interaction between the tumor and the immune system.

Important: PD-1 blockade is not universally effective. Response depends on tumor biology, immune context, disease setting, prior treatment, biomarkers and other factors. A positive KEYNOTE trial therefore identifies a specific population and treatment strategy—not a universal cancer treatment.

2. The KEYNOTE Revolution: A Clinical Timeline

Era	Representative KEYNOTE Trials	Major Scientific Development
2014–2016	KEYNOTE-001, KEYNOTE-006	Proof that PD-1 blockade can generate durable responses in advanced cancer.
2016–2018	KEYNOTE-010, KEYNOTE-024	PD-L1 expression becomes clinically important for patient selection.
2018–2020	KEYNOTE-189, KEYNOTE-407, KEYNOTE-048	Combination chemo-immunotherapy becomes a major treatment paradigm.
2020–2022	KEYNOTE-177, KEYNOTE-426, KEYNOTE-826	Biomarker-driven and combination strategies expand across tumor types.
2021–2024	KEYNOTE-522, KEYNOTE-564, KEYNOTE-671	Immunotherapy moves into neoadjuvant, perioperative and adjuvant settings.
2024–2026	Long-term KEYNOTE analyses and newer combination studies	Focus shifts toward durability, survival, treatment sequencing and biomarker refinement.

3. The 25 Landmark KEYNOTE Trials

#	Trial	Cancer	Landmark contribution
1	KEYNOTE-001	Multiple advanced cancers; especially NSCLC	Early clinical proof that pembrolizumab could produce durable responses, helping establish PD-1 blockade as a viable anticancer strategy.
2	KEYNOTE-006	Advanced melanoma	Demonstrated superior outcomes versus ipilimumab and helped establish PD-1 blockade as a central melanoma treatment.
3	KEYNOTE-010	Previously treated NSCLC	Established a survival advantage for pembrolizumab versus docetaxel in PD-L1-positive NSCLC.
4	KEYNOTE-024	Advanced NSCLC	Landmark demonstration that highly PD-L1-positive tumors could benefit from first-line pembrolizumab monotherapy.
5	KEYNOTE-042	Advanced NSCLC	Expanded evaluation of pembrolizumab monotherapy to tumors with lower PD-L1 expression.
6	KEYNOTE-189	Metastatic nonsquamous NSCLC	Helped establish pembrolizumab plus platinum/pemetrexed chemotherapy as a major first-line strategy.
7	KEYNOTE-407	Metastatic squamous NSCLC	Extended the chemo-immunotherapy paradigm to squamous NSCLC.
8	KEYNOTE-048	Recurrent/metastatic head and neck squamous cell carcinoma	Established pembrolizumab alone or with chemotherapy as a major first-line treatment strategy in selected patients.
9	KEYNOTE-045	Advanced urothelial carcinoma	Demonstrated an overall-survival advantage over chemotherapy after platinum treatment.
10	KEYNOTE-177	MSI-H/dMMR metastatic colorectal cancer	One of the clearest demonstrations that tumor biology can determine immunotherapy sensitivity across an anatomical cancer type.
11	KEYNOTE-158	Multiple advanced solid tumors	Provided important evidence for biomarker-selected pembrolizumab treatment across tumor types, including MSI-H/dMMR disease.
12	KEYNOTE-426	Advanced clear-cell renal cell carcinoma	Established pembrolizumab plus axitinib as a powerful first-line combination strategy.
13	KEYNOTE-564	High-risk clear-cell renal cell carcinoma after surgery	Established adjuvant pembrolizumab and later demonstrated an overall-survival benefit.
14	KEYNOTE-522	Early-stage triple-negative breast cancer	Moved pembrolizumab into neoadjuvant and adjuvant treatment and demonstrated improved event-free and overall survival.
15	KEYNOTE-355	Advanced/metastatic triple-negative breast cancer	Demonstrated the importance of PD-L1 CPS selection in metastatic TNBC treated with pembrolizumab plus chemotherapy.
16	KEYNOTE-826	Persistent, recurrent or metastatic cervical cancer	Established pembrolizumab plus chemotherapy as an important first-line strategy in PD-L1-positive disease.
17	KEYNOTE-590	Advanced esophageal cancer	Established a major chemo-immunotherapy strategy in advanced esophageal cancer.
18	KEYNOTE-775 / Study 309	Advanced/recurrent endometrial cancer	Established pembrolizumab plus lenvatinib as an important treatment for previously treated advanced endometrial cancer, particularly in pMMR disease.
19	KEYNOTE-018	Advanced gastric cancer	Early evidence demonstrating pembrolizumab activity in gastric cancer and contributing to the development of later combination strategies.
20	KEYNOTE-811	HER2-positive gastric/GEJ adenocarcinoma	Demonstrated the potential of combining PD-1 blockade with HER2-directed therapy and chemotherapy.
21	KEYNOTE-091 / PEARLS	Resected NSCLC	Provided important evidence for adjuvant pembrolizumab after surgical resection.
22	KEYNOTE-671	Resectable early-stage NSCLC	Moved pembrolizumab into perioperative therapy: neoadjuvant chemo-immunotherapy followed by surgery and adjuvant pembrolizumab.
23	KEYNOTE-716	Resected stage II melanoma	Extended adjuvant PD-1 blockade into earlier-stage melanoma.
24	KEYNOTE-054	Resected high-risk melanoma	Demonstrated the value of adjuvant pembrolizumab in reducing recurrence after surgery.
25	KEYNOTE-859	HER2-negative advanced gastric/GEJ adenocarcinoma	Further established pembrolizumab plus chemotherapy as an important first-line gastric cancer strategy, with benefit influenced by PD-L1 expression.

4. Detailed Analysis of the Landmark Trials

4.1 KEYNOTE-001 — The proof-of-concept trial

Why it mattered: KEYNOTE-001 helped demonstrate that blocking PD-1 could produce clinically meaningful and durable tumor responses.

It was an early foundational study rather than a conventional confirmatory phase 3 comparison. Its importance lies in demonstrating that immune checkpoint inhibition could generate responses lasting far beyond the expected duration of many conventional therapies.

Historical significance: KEYNOTE-001 helped provide the clinical foundation for the subsequent randomized KEYNOTE program.

4.2 KEYNOTE-006 — PD-1 blockade transforms melanoma

KEYNOTE-006 compared pembrolizumab with ipilimumab in advanced melanoma.

The trial became one of the landmark demonstrations that PD-1 inhibition could outperform CTLA-4 inhibition in a major solid tumor setting.

The importance extends beyond melanoma: it established the concept that checkpoint blockade can produce prolonged disease control in some patients even when metastatic cancer was previously considered difficult to control durably.

4.3 KEYNOTE-010 — PD-L1 becomes clinically actionable

KEYNOTE-010 studied pembrolizumab versus docetaxel in previously treated NSCLC with PD-L1 expression.

The trial helped move PD-L1 from a biological research marker toward a clinically relevant treatment-selection biomarker.

Lesson: Immunotherapy does not operate independently of tumor biology. Biomarker enrichment can substantially change the probability of benefit.

4.4 KEYNOTE-024 — The PD-L1 ≥50% breakthrough

KEYNOTE-024 was a pivotal first-line phase 3 study in advanced NSCLC with high PD-L1 expression.

Patients with PD-L1 tumor proportion score of at least 50% experienced significantly better progression-free and overall survival with pembrolizumab than with platinum-based chemotherapy.

The study helped establish a new model of oncology treatment: test the tumor first, then select immunotherapy according to biomarker-defined probability of benefit.

Key result: In the original analysis, 6-month overall survival was approximately 80% with pembrolizumab versus 72% with chemotherapy; the hazard ratio for death was approximately 0.60.

4.5 KEYNOTE-042 — Broadening PD-L1 eligibility

KEYNOTE-042 evaluated pembrolizumab monotherapy in previously untreated advanced NSCLC with PD-L1 expression of at least 1%.

Its interpretation is more nuanced than KEYNOTE-024. The overall population showed an OS benefit, but the magnitude of benefit was greatest in patients with higher PD-L1 expression.

Lesson: A biomarker threshold can identify a population, but lowering the threshold may dilute treatment effect. The meaning of a positive biomarker is therefore quantitative, not simply binary.

4.6 KEYNOTE-189 — The chemo-immunotherapy revolution

KEYNOTE-189 combined pembrolizumab with pemetrexed and platinum chemotherapy in previously untreated metastatic nonsquamous NSCLC without EGFR or ALK sensitizing alterations.

The trial fundamentally changed first-line NSCLC treatment by showing that pembrolizumab could add substantial benefit to chemotherapy rather than being restricted to monotherapy in highly PD-L1-positive tumors.

Strategic significance: The trial helped establish combination therapy as a central immunotherapy paradigm.

4.7 KEYNOTE-407 — Extending the paradigm to squamous NSCLC

KEYNOTE-407 evaluated pembrolizumab plus carboplatin and a taxane in metastatic squamous NSCLC.

The combination improved both progression-free and overall survival compared with chemotherapy alone. The original trial reported median OS of 15.9 months versus 11.3 months, with a hazard ratio for death of 0.64.

Lesson: The chemo-immunotherapy strategy was not limited to nonsquamous NSCLC.

4.8 KEYNOTE-048 — Head and neck cancer enters the immunotherapy era

KEYNOTE-048 established pembrolizumab-containing strategies as important first-line options in recurrent or metastatic head and neck squamous cell carcinoma.

The trial also highlighted the importance of PD-L1 combined positive score (CPS), illustrating that PD-L1 measurement is not identical across tumor types.

4.9 KEYNOTE-045 — Urothelial carcinoma

KEYNOTE-045 compared pembrolizumab with chemotherapy after platinum-based therapy in advanced urothelial carcinoma.

The study demonstrated improved overall survival and helped establish PD-1 blockade as a major treatment option in previously treated bladder/urothelial cancer.

Lesson: Pembrolizumab activity extended beyond melanoma and lung cancer into traditionally chemotherapy-dominated cancers.

4.10 KEYNOTE-177 — The tumor-biology revolution

KEYNOTE-177 is among the most conceptually important KEYNOTE trials.

Instead of selecting patients primarily by anatomical tumor site, it selected patients with MSI-high (MSI-H) or mismatch-repair deficient (dMMR) metastatic colorectal cancer.

First-line pembrolizumab produced substantially longer PFS than chemotherapy. Longer follow-up subsequently demonstrated durable benefit: median PFS was approximately 16.5 months versus 8.2 months, while the later analysis reported median OS of 77.5 months versus 36.7 months despite extensive crossover.

Why this matters: MSI-H/dMMR status identifies a biological phenotype associated with high mutation burden and increased tumor immunogenicity. The trial helped establish the principle that tumor biology can sometimes be more informative than tumor location.

4.11 KEYNOTE-158 — Toward tumor-agnostic immunotherapy

KEYNOTE-158 evaluated pembrolizumab across multiple advanced solid tumors and became an important component of the evidence base for biomarker-selected treatment.

The broader lesson was the emergence of tumor-agnostic oncology: a molecular characteristic such as MSI-H/dMMR can sometimes identify patients likely to benefit regardless of the organ in which the cancer originated.

4.12 KEYNOTE-426 — Immunotherapy plus targeted therapy

KEYNOTE-426 combined pembrolizumab with the VEGF-targeting tyrosine kinase inhibitor axitinib in previously untreated advanced clear-cell renal cell carcinoma.

The combination improved survival and disease control compared with sunitinib.

Longer follow-up maintained the advantage, supporting pembrolizumab plus axitinib as a major first-line strategy in advanced clear-cell RCC.

4.13 KEYNOTE-564 — Immunotherapy after surgery

KEYNOTE-564 was a major milestone because pembrolizumab was moved from metastatic treatment into the adjuvant setting after surgery for patients with increased risk of recurrence from clear-cell renal cell carcinoma.

At longer follow-up, pembrolizumab demonstrated a statistically significant overall-survival advantage. The reported hazard ratio for death was approximately 0.62.

Lesson: Immunotherapy can potentially eliminate microscopic residual disease before it becomes clinically detectable metastatic cancer.

4.14 KEYNOTE-522 — Immunotherapy enters curative-intent breast cancer

KEYNOTE-522 evaluated pembrolizumab with neoadjuvant chemotherapy followed by surgery and adjuvant pembrolizumab in stage II–III triple-negative breast cancer.

At the 36-month analysis, event-free survival was approximately 84.5% with pembrolizumab versus 76.8% with placebo, with a hazard ratio of 0.63.

Importantly, later overall-survival results confirmed a significant survival benefit. Five-year overall survival was approximately 86.6% with pembrolizumab versus 81.7% with chemotherapy alone.

Landmark significance: KEYNOTE-522 helped establish immunotherapy as part of curative-intent therapy rather than simply treatment for metastatic disease.

4.15 KEYNOTE-355 — Biomarker selection in metastatic TNBC

KEYNOTE-355 tested pembrolizumab plus chemotherapy in metastatic triple-negative breast cancer.

The benefit was strongly linked to PD-L1 expression measured using CPS, particularly in patients with higher CPS values.

Lesson: The predictive value of PD-L1 is context-dependent. PD-L1 TPS, CPS and other biomarker systems should not be treated as interchangeable.

4.16 KEYNOTE-826 — Cervical cancer

KEYNOTE-826 evaluated pembrolizumab plus chemotherapy, with or without bevacizumab, in persistent, recurrent or metastatic cervical cancer.

The trial demonstrated improved PFS and OS, particularly in the PD-L1-positive population.

The study further expanded the role of pembrolizumab into gynecologic oncology.

4.17 KEYNOTE-590 — Esophageal cancer

KEYNOTE-590 evaluated pembrolizumab plus chemotherapy in advanced esophageal cancer.

The trial contributed to the growing body of evidence that PD-1 blockade can synergize with chemotherapy in gastrointestinal malignancies.

4.18 KEYNOTE-775 — Pembrolizumab plus lenvatinib

KEYNOTE-775 evaluated pembrolizumab plus the multikinase inhibitor lenvatinib versus physician's-choice chemotherapy in advanced endometrial cancer.

The combination improved PFS and OS in the overall study population, including patients whose tumors were mismatch-repair proficient.

Scientific significance: This provided an important example of combining immune checkpoint inhibition with antiangiogenic/kinase-targeted therapy.

4.19 KEYNOTE-018 — Early gastric cancer development

KEYNOTE-018 was part of the early development program demonstrating pembrolizumab activity in gastric cancer.

Although subsequent trials were more decisive for establishing modern gastric-cancer treatment, early KEYNOTE studies helped define the role of PD-L1 expression and response heterogeneity.

4.20 KEYNOTE-811 — HER2-positive gastric/GEJ cancer

KEYNOTE-811 examined pembrolizumab added to trastuzumab and chemotherapy in HER2-positive gastric or gastroesophageal-junction adenocarcinoma.

This trial illustrates a particularly important modern oncology concept: immune therapy can be combined with molecularly targeted therapy.

The strategy subsequently demonstrated improvements in progression-free and overall survival in the appropriate population.

4.21 KEYNOTE-091 — Adjuvant NSCLC

KEYNOTE-091, also known as PEARLS, evaluated adjuvant pembrolizumab after complete resection of NSCLC.

The study helped establish that checkpoint inhibition could have a role after surgery even when patients were no longer known to have measurable disease.

4.22 KEYNOTE-671 — Perioperative lung cancer

KEYNOTE-671 took the perioperative concept further.

Patients with resectable early-stage NSCLC received neoadjuvant pembrolizumab plus chemotherapy, surgery, and subsequent adjuvant pembrolizumab.

The trial significantly improved event-free survival, major pathological response and pathological complete response. Subsequent analyses demonstrated an overall-survival benefit.

Strategic significance: This represents the movement of immunotherapy toward the beginning of the cancer journey rather than waiting until metastatic relapse.

4.23 KEYNOTE-716 — Earlier melanoma

KEYNOTE-716 moved pembrolizumab into the adjuvant treatment of resected stage II melanoma.

This was another example of the broader shift from treating established metastatic disease toward preventing recurrence in patients who have undergone apparently curative surgery.

4.24 KEYNOTE-054 — High-risk melanoma after surgery

KEYNOTE-054 demonstrated that adjuvant pembrolizumab could reduce the risk of recurrence in patients with completely resected high-risk melanoma.

It reinforced the idea that immune checkpoint blockade can target microscopic residual disease that is not visible on conventional imaging.

4.25 KEYNOTE-859 — Expanding gastric cancer immunotherapy

KEYNOTE-859 evaluated pembrolizumab plus chemotherapy in HER2-negative advanced gastric or gastroesophageal-junction adenocarcinoma.

The trial reinforced the role of first-line chemo-immunotherapy while also illustrating an increasingly important principle: treatment effect can vary according to PD-L1 expression.

5. The Biomarker Revolution

One of the most important lessons from the KEYNOTE program is that “immunotherapy-responsive cancer” is not a single biological category.

Biomarker	What it measures	Why it matters
PD-L1 TPS	Percentage of viable tumor cells expressing PD-L1	Important in selected NSCLC treatment decisions.
PD-L1 CPS	PD-L1-positive tumor and immune cells relative to viable tumor cells	Used in several cancers including gastric, cervical and head/neck cancers.
MSI-H	High microsatellite instability	Can identify tumors with strong sensitivity to immune checkpoint blockade.
dMMR	Deficient DNA mismatch-repair function	Strongly associated with MSI-H biology and immunotherapy sensitivity.
TMB-H	High tumor mutational burden	May identify tumors with increased neoantigen generation, although predictive utility is context-dependent.
Genomic alterations	Driver mutations such as EGFR, ALK and others	Some oncogenic drivers can change the preferred treatment sequence and the expected value of immunotherapy.

Clinical caution: PD-L1 is not a universal on/off switch. Different cancers use different assays, scoring systems and thresholds. A patient's treatment decision should therefore be based on the specific cancer, stage, biomarker assay and approved indication rather than on a generic statement that “PD-L1 positive means Keytruda works.”

6. From Metastatic Disease to Curative-Intent Treatment

The history of pembrolizumab can be viewed as a progression through increasingly earlier stages of disease.

Stage of development	Representative trials	Clinical concept
Advanced/metastatic	KEYNOTE-006, 010, 024, 045	Treat established advanced cancer.
First-line metastatic	KEYNOTE-189, 407, 426, 826	Use immunotherapy early and combine it with chemotherapy or targeted therapy.
Neoadjuvant	KEYNOTE-522, 671	Activate systemic immunity before definitive surgery.
Adjuvant	KEYNOTE-054, 564, 716, 091	Treat microscopic residual disease after surgery.
Perioperative	KEYNOTE-671 and related studies	Integrate immunotherapy across the preoperative and postoperative treatment period.

This evolution is arguably one of the most important achievements of the KEYNOTE program.

The therapeutic objective has shifted from “shrink metastatic tumors” toward “prevent recurrence and potentially improve cure rates.”

7. Why Keytruda Combinations Became Important

Pembrolizumab is increasingly used as part of combination strategies rather than as a stand-alone drug.

Combination	Representative KEYNOTE trials	Therapeutic rationale
PD-1 + chemotherapy	KEYNOTE-189, 407, 522, 590, 826, 859	Chemotherapy may produce tumor-cell death and alter antigen presentation while pembrolizumab activates immune responses.
PD-1 + targeted therapy	KEYNOTE-426	Targeted therapy may modify tumor vasculature or signaling while immunotherapy activates antitumor immunity.
PD-1 + antiangiogenic therapy	KEYNOTE-775	Antiangiogenic therapy may alter the tumor microenvironment and potentially improve immune-cell access/function.
PD-1 + HER2 therapy	KEYNOTE-811	Combines immune checkpoint inhibition with molecularly targeted HER2 treatment.

8. Long-Term Responders: The Most Important Immunotherapy Signal

One of the distinctive features of successful immune checkpoint blockade is that a subset of patients can experience unusually durable disease control.

This creates an important distinction between conventional measures of treatment activity and immunotherapy outcomes.

• Response rate asks how many tumors shrink.
• PFS asks how long patients remain without progression or death.
• OS asks whether patients live longer.
• Duration of response asks how long tumor responses persist.
• Long-term survival asks whether a subset of patients may remain alive for many years after treatment.

KEYNOTE-177 provides an especially useful example. With more than five years of follow-up, pembrolizumab-treated MSI-H/dMMR metastatic colorectal cancer patients had substantially longer median OS and durable responses compared with chemotherapy, despite extensive crossover from the control group.

This does not mean every patient becomes a long-term survivor. Rather, it demonstrates that the survival curve can contain a clinically important subset of patients with prolonged disease control.

9. What the KEYNOTE Trials Do Not Prove

The success of pembrolizumab has sometimes generated overly broad interpretations. The KEYNOTE evidence does not justify the following conclusions:

• Keytruda works for every cancer.
• PD-L1 positivity guarantees response.
• MSI-H/dMMR guarantees complete remission.
• Immunotherapy is always better than chemotherapy.
• Combining Keytruda with additional drugs automatically improves outcomes.
• A response in metastatic disease means the cancer is cured.
• Results from one cancer type can automatically be transferred to another.
• Results from a clinical trial justify off-label combinations outside an evidence-supported setting.

Safety: Pembrolizumab can cause immune-mediated adverse events involving organs such as the thyroid, liver, lungs, colon, kidneys, skin and other tissues. Severe or life-threatening immune-related toxicity can occur. Treatment decisions require oncology supervision and appropriate monitoring.

10. How to Interpret a KEYNOTE Trial

For patients, clinicians, researchers and health-information writers, a useful framework is to ask ten questions:

1. What cancer was studied?
2. What stage was the cancer?
3. Was treatment first-line or later-line?
4. What biomarker was required?
5. What was the control treatment?
6. Was the trial randomized?
7. What was the primary endpoint?
8. Did the treatment improve OS, PFS, EFS or another endpoint?
9. How large was the absolute benefit?
10. What were the toxicities and limitations?

This prevents a common error in online cancer information: quoting a response rate without explaining the patient population or comparator.

11. Relative Risk vs Absolute Benefit

Another important principle is distinguishing a hazard ratio from the absolute clinical benefit.

A hazard ratio of 0.60 does not mean that 40% of patients will be cured. It means that, under the statistical model used for the trial, the instantaneous risk of the relevant event was approximately 40% lower in the treatment group than in the control group.

For patients, the most useful questions are often:

• How many patients were alive at a specified time?
• How many remained progression-free?
• How much longer did patients live?
• How many experienced serious treatment toxicity?
• How many patients stopped treatment because of adverse events?
• How durable were responses?

12. The KEYNOTE Program as a Model of Precision Oncology

The evolution of pembrolizumab illustrates several major transitions in oncology.

Transition 1: From organ-based treatment to biomarker-guided treatment

Traditional oncology largely organized treatment according to the anatomical location of the tumor.

Modern immuno-oncology increasingly asks:

What biological features make this tumor vulnerable to immune attack?

Transition 2: From metastatic treatment to recurrence prevention

KEYNOTE-054, KEYNOTE-564, KEYNOTE-522 and KEYNOTE-671 demonstrate the movement of checkpoint blockade into earlier disease stages.

Transition 3: From monotherapy to rational combinations

KEYNOTE-189, KEYNOTE-407, KEYNOTE-426, KEYNOTE-775 and KEYNOTE-811 illustrate different approaches to combination therapy.

Transition 4: From response to durability

Immunotherapy research increasingly emphasizes durable disease control and long-term survival rather than short-term tumor shrinkage alone.

13. Keytruda and the Future of Cancer Immunotherapy

The next generation of pembrolizumab research is likely to focus less on the simple question “Does PD-1 blockade work?” and more on:

• Which patients benefit most?
• Who can safely avoid chemotherapy?
• Who needs combination therapy?
• Can treatment be shortened without sacrificing efficacy?
• Can biomarkers predict resistance before treatment starts?
• How should immunotherapy be sequenced with targeted therapies?
• How should minimal residual disease be integrated into treatment decisions?
• Can circulating tumor DNA identify patients who need escalation or de-escalation?
• How can immune-related toxicity be reduced?
• How can primary resistance and acquired resistance be overcome?

These questions are likely to define the next generation of KEYNOTE and immunotherapy research.

14. Landmark KEYNOTE Trials: The Big Picture

Scientific question	Key KEYNOTE examples	What changed
Does PD-1 blockade work?	001, 006	Established proof of concept and durable responses.
Can biomarkers select patients?	010, 024, 042	PD-L1 became clinically relevant.
Can immunotherapy combine with chemotherapy?	189, 407, 590, 826, 859	Chemo-immunotherapy became a major treatment paradigm.
Can tumor biology transcend tumor location?	177, 158	MSI-H/dMMR became a powerful tumor-agnostic concept.
Can immunotherapy combine with targeted therapy?	426, 775, 811	Combination precision oncology expanded.
Can immunotherapy prevent recurrence?	054, 564, 716, 091	Adjuvant immunotherapy entered multiple cancers.
Can immunotherapy improve cure-oriented treatment?	522, 671	Neoadjuvant/perioperative immunotherapy became a major strategy.

15. Conclusion

The KEYNOTE program represents one of the most important clinical-development programs in modern oncology.

Its importance is not attributable to a single trial. Rather, the trials collectively demonstrate the evolution of cancer immunotherapy from an experimental treatment for advanced disease into a broad therapeutic platform.

KEYNOTE-006 helped establish PD-1 blockade in melanoma.

KEYNOTE-024 demonstrated the power of biomarker-selected first-line immunotherapy in NSCLC.

KEYNOTE-189 and KEYNOTE-407 helped establish chemo-immunotherapy.

KEYNOTE-177 demonstrated the extraordinary importance of MSI-H/dMMR biology.

KEYNOTE-426, 775 and 811 demonstrated the potential of rational combinations.

KEYNOTE-522, 564, 671 and related trials moved immunotherapy increasingly toward curative-intent treatment.

The overarching lesson is therefore larger than Keytruda itself:

The future of oncology is increasingly defined by matching the right biological vulnerability with the right treatment at the right stage of disease.

Checkpoint inhibitors such as pembrolizumab are an important part of that transition—but their effectiveness depends on patient selection, tumor biology, treatment setting, combinations, resistance mechanisms and careful management of immune-related toxicity.

16. Frequently Asked Questions

What is the most important Keytruda trial?

There is no single universally “most important” trial. KEYNOTE-006 was historically important in melanoma; KEYNOTE-024 was transformative in biomarker-selected NSCLC; KEYNOTE-189 changed metastatic nonsquamous NSCLC; KEYNOTE-177 demonstrated the importance of MSI-H/dMMR biology; and KEYNOTE-522 and KEYNOTE-671 demonstrated the movement of pembrolizumab into curative-intent treatment.

Which KEYNOTE trial established Keytruda in lung cancer?

Several trials were important. KEYNOTE-024 was particularly influential because it demonstrated first-line pembrolizumab monotherapy in advanced NSCLC with high PD-L1 expression. KEYNOTE-189 and KEYNOTE-407 subsequently established major chemo-immunotherapy approaches.

Which KEYNOTE trial is most important for MSI-H colorectal cancer?

KEYNOTE-177 is the landmark randomized phase 3 trial in previously untreated MSI-H/dMMR metastatic colorectal cancer.

Does PD-L1 positivity mean Keytruda will work?

No. PD-L1 is a predictive biomarker in selected clinical contexts, but it is not a guarantee of response. The relevant assay, scoring method, threshold, tumor type, disease stage and treatment regimen all matter.

Can Keytruda cure cancer?

Some patients treated with pembrolizumab can experience very durable disease control, and immunotherapy has demonstrated survival and recurrence benefits in curative-intent settings. However, Keytruda should not be described as a universal cure for cancer.

Is Keytruda chemotherapy?

No. Pembrolizumab is an immune checkpoint inhibitor targeting PD-1. It is frequently combined with chemotherapy, but it is pharmacologically and biologically different from conventional cytotoxic chemotherapy.

Why is Keytruda sometimes combined with chemotherapy?

Combination therapy can produce complementary effects. Chemotherapy can reduce tumor burden and alter tumor-immune interactions, while pembrolizumab can restore T-cell activity. The clinical benefit, however, must be demonstrated in the specific cancer and treatment setting.

Why are some Keytruda trials positive while others are not?

Immune responsiveness varies considerably between cancers and patients. Differences in tumor biology, PD-L1 expression, mutation burden, immune-cell infiltration, prior treatment, disease stage, combination partner and mechanisms of immune resistance can all influence outcomes.

17. Selected References

1. Robert C, Schachter J, Long GV, et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. New England Journal of Medicine. 2015;372:2521–2532. KEYNOTE-006.
2. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non–Small-Cell Lung Cancer. New England Journal of Medicine. 2016;375:1823–1833. KEYNOTE-024.
3. Gandhi L, Rodríguez-Abreu D, Gadgeel S, et al. Pembrolizumab plus Chemotherapy in Metastatic Non–Small-Cell Lung Cancer. New England Journal of Medicine. 2018;378:2078–2092. KEYNOTE-189.
4. Paz-Ares L, Luft A, Vicente D, et al. Pembrolizumab plus Chemotherapy for Squamous Non–Small-Cell Lung Cancer. New England Journal of Medicine. 2018;379:2040–2051. KEYNOTE-407.
5. André T, Shiu KK, Kim TW, et al. Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer. New England Journal of Medicine. 2020;383:2207–2218. KEYNOTE-177.
6. André T, Shiu KK, Kim TW, et al. Pembrolizumab versus chemotherapy in MSI-H/dMMR metastatic colorectal cancer: final analysis. The Lancet Oncology. 2022.
7. Long GV, Blank CU, Ribas A, et al. Adjuvant Pembrolizumab versus Placebo in Resected Stage II Melanoma. KEYNOTE-716.
8. Schmid P, Cortes J, Dent R, et al. Event-free Survival with Pembrolizumab in Early Triple-Negative Breast Cancer. New England Journal of Medicine. 2022;386:556–567. KEYNOTE-522.
9. Schmid P, Cortes J, Dent R, et al. Overall Survival with Pembrolizumab in Early-Stage Triple-Negative Breast Cancer. New England Journal of Medicine. 2024;391:1981–1991.
10. Choueiri TK, Tomczak P, Park SH, et al. Overall Survival with Adjuvant Pembrolizumab in Renal-Cell Carcinoma. New England Journal of Medicine. 2024;390:1359–1371. KEYNOTE-564.
11. Wakelee H, Liberman M, Kato T, et al. Perioperative Pembrolizumab for Early-Stage Non–Small-Cell Lung Cancer. New England Journal of Medicine. 2023;389:491–503. KEYNOTE-671.
12. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma. New England Journal of Medicine. 2019;380:1116–1127. KEYNOTE-426.
13. Makker V, Colombo N, Casado Herráez A, et al. Lenvatinib plus Pembrolizumab for Advanced Endometrial Cancer. New England Journal of Medicine. 2022;386:437–448. KEYNOTE-775.
14. Janjigian YY, Kawazoe A, Bai Y, et al. Pembrolizumab in HER2-Positive Gastric Cancer. New England Journal of Medicine. 2024;391:1360–1362. KEYNOTE-811 updated evidence.
15. FDA. Pembrolizumab clinical and pharmacogenomic biomarker information. U.S. Food and Drug Administration.

Medical disclaimer: This article is an educational review of published clinical-trial evidence. It is not medical advice and does not replace evaluation by a qualified oncologist. Treatment selection should consider cancer type, stage, histology, biomarkers, molecular alterations, prior treatment, performance status, comorbidities, contraindications, toxicity risk and applicable clinical guidelines.

Editorial note: Trial results are reported for their studied populations. Hazard ratios, response rates and survival estimates should not be interpreted as guarantees for an individual patient.