In HR-Positive Metastatic Breast Cancer, Pembrolizumab + Chemotherapy Slightly Delayed Progression but Did Not Extend Survival: KEYNOTE-B49

Immunotherapy in Hormone Receptor-Positive Metastatic Breast Cancer: KEYNOTE-B49 Delayed Progression but Did Not Change Survival

In hormone receptor-positive, HER2-negative metastatic breast cancer, adding the immunotherapy drug pembrolizumab to chemotherapy delayed disease progression somewhat but did not extend survival. Results of the phase 3 KEYNOTE-B49 trial were presented as a late-breaking abstract (LBA51) at ESMO 2026. In 342 PD-L1-positive patients, median progression-free survival increased from 6.0 to 6.7 months (HR 0.74), while overall survival remained similar (21.0 vs 22.2 months; HR 1.04). We have previously covered pembrolizumab, new treatment options in hormone receptor-positive breast cancer and the ESMO 2026 agenda.

Why does this matter?

Hormone receptor-positive (HR-positive), HER2-negative breast cancer accounts for about 70% of all breast cancers. In metastatic disease, the backbone of treatment is endocrine therapy combined with CDK4/6 inhibitors. Over time, however, the disease develops resistance to endocrine therapy, and many patients eventually need chemotherapy or antibody–drug conjugates.

Immunotherapy combined with chemotherapy has become standard in triple-negative breast cancer. HR-positive breast cancer, by contrast, is considered immunologically "cold": there are few immune cells within the tumor, and PD-L1 expression is less common. In early-stage disease, preoperative immunotherapy had been shown to increase the pathological complete response rate; KEYNOTE-B49 was designed to answer whether this approach translates into longer survival in metastatic HR-positive disease.

What did the KEYNOTE-B49 trial show?

KEYNOTE-B49 is a phase 3 trial comparing the addition of pembrolizumab versus placebo to chemotherapy in PD-L1-positive HR-positive/HER2-negative metastatic breast cancer that progressed after endocrine therapy. Pembrolizumab improved progression-free survival significantly but modestly (6.7 vs 6.0 months) and provided long-term disease control in a small number of patients; however, it did not improve overall survival and increased adverse events.

How was the trial conducted?

The trial was originally planned with about 800 patients; however, because PD-L1 positivity proved less common than expected in HR-positive breast cancer, a protocol amendment reduced the sample size to 342.

Results

Progression-free survival

In the PD-L1 CPS ≥1 population, median progression-free survival was 6.7 months in the pembrolizumab arm and 6.0 months in the placebo arm (HR 0.74; 95% CI 0.58–0.95; one-sided p=0.0089). This corresponds to an approximately 26% reduction in the risk of disease progression; however, the difference in median times is only about 3 weeks. In patients with PD-L1 CPS ≥10, the difference appears larger (7.5 vs 4.4 months; HR 0.59), but this subgroup is small and was not part of the prespecified formal statistical testing.

Although the medians show a small difference, the tails of the curves tell a different story: at 24 months, 15% of patients in the pembrolizumab arm and 4% in the placebo arm were still progression-free. This suggests that immunotherapy can provide long-term disease control in a small number of patients with HR-positive breast cancer as well, but that there is not yet a biomarker able to identify these patients in advance.

Overall survival

In the final analysis, median overall survival was 21.0 months in the pembrolizumab arm and 22.2 months in the placebo arm (HR 1.04; 95% CI 0.81–1.33; p=0.62). There was no difference in the CPS ≥10 subgroup either (22.9 vs 22.5 months; HR 0.82; 36 patients per arm). In other words, the delay in progression did not translate into a survival gain.

Safety

Grade 3 or higher treatment-related adverse events were more frequent in the pembrolizumab arm (37.6% vs 32.7%), and the rate of discontinuation due to adverse events doubled (11.2% vs 5.4%). Pembrolizumab can cause immune-mediated adverse events in organs such as the thyroid gland, lungs, bowel, liver and skin (side effects of immunotherapy); some of these, such as thyroid or pituitary insufficiency, may be permanent. Less often, the kidneys may also be affected.

How should the results be interpreted?

Strengths

• Double-blind, placebo-controlled phase 3 design; progression-free survival was assessed by blinded independent central review.
• It reflects today's patient population: nearly all patients had previously received a CDK4/6 inhibitor.
• PD-L1 was assessed by a central laboratory, and the chemotherapy options reflected routine practice.
• The overall survival result was reported clearly, even though it was negative.

Points to keep in mind

• No survival benefit: In metastatic disease, a small gain in progression-free survival has limited clinical value if it does not translate into longer survival while adverse events increase.
• The absolute difference is small: The difference in median progression-free survival is about 3 weeks.
• Reduced sample size: Far fewer patients were enrolled than planned, which limits the power of subgroup analyses in particular.
• CPS ≥10 subgroup: The seemingly larger benefit rests on a small, exploratory analysis; no interaction analysis by PD-L1 level was reported.
• Subsequent treatments: Effective later-line treatments such as antibody–drug conjugates may have masked an overall survival difference.
• Source limitations: Response rate, duration of response and details of immune-mediated adverse events have not yet appeared in a peer-reviewed publication.

What does this mean in practice?

• The standard does not change: In HR-positive/HER2-negative metastatic breast cancer after endocrine therapy and CDK4/6 inhibitors, the main options for suitable patients remain targeted therapies, new endocrine therapy combinations, chemotherapy, and antibody–drug conjugates such as sacituzumab govitecan or trastuzumab deruxtecan.
• Immunotherapy should not be routinely added to chemotherapy: Because no survival benefit was shown and adverse events increased, this combination is not recommended in HR-positive disease based on current data.
• The right patients need to be identified: The difference at 24 months suggests that some patients derive clear benefit from immunotherapy. The value of biomarkers such as high PD-L1, tumor-infiltrating lymphocyte density, the basal-like molecular subtype or high tumor mutational burden should be investigated.
• Early-stage disease is a separate question: The role of preoperative immunotherapy in high-risk early-stage ER-positive disease will become clearer with event-free survival results; this finding in metastatic disease cannot be directly extrapolated to the early-stage setting.

Practical advice for patients and families

• If you have HR-positive metastatic breast cancer (metastatic breast cancer treatment), be aware that immunotherapy is not currently a standard option for you; a "positive result" in the news does not mean that survival was extended.
• If your disease has progressed after endocrine therapy and a CDK4/6 inhibitor, ask whether your tumor has been tested for alterations such as ESR1, PIK3CA and AKT1 and for HER2 level; these determine which targeted therapies may be suitable for you (beyond CDK4/6 inhibitors).
• While receiving chemotherapy, contact your care team right away if you develop symptoms such as fever, diarrhea or shortness of breath (chemotherapy and fever).
• If you have the opportunity to join a clinical trial that includes immunotherapy, you can discuss it with your care team and, if needed, seek a second opinion.
• Exercise and rehabilitation during treatment can support your quality of life.

Frequently asked questions

Does immunotherapy work in hormone receptor-positive breast cancer?

To a limited extent. In the KEYNOTE-B49 trial, adding pembrolizumab to chemotherapy in PD-L1-positive, hormone receptor-positive metastatic breast cancer extended progression-free survival from 6.0 to 6.7 months and provided long-term disease control in a small number of patients; however, it did not extend survival and increased adverse events.

Will the KEYNOTE-B49 results change the standard of care?

Not in their current form. Because there is no overall survival benefit, the absolute difference is small and adverse events increase, pembrolizumab + chemotherapy is not expected to enter routine use in HR-positive/HER2-negative metastatic breast cancer.

Is immunotherapy more effective when PD-L1 is high (CPS ≥10)?

The progression-free survival difference appears larger in this group (7.5 vs 4.4 months), but overall survival is similar and the subgroup is small (36 patients per arm). It is therefore not sufficient to draw a firm conclusion.

Can pembrolizumab be used for hormone receptor-positive breast cancer in Turkey?

Pembrolizumab is licensed in Turkey, but it has no approved indication and no SGK reimbursement in hormone receptor-positive/HER2-negative breast cancer. In breast cancer, its use is limited to triple-negative disease.

Glossary

HR-positive/HER2-negative breast cancer

The most common type of breast cancer, in which the cells carry hormone (estrogen and/or progesterone) receptors and do not overproduce the HER2 protein.

Pembrolizumab

An immunotherapy drug that releases the PD-1 brake that prevents the immune system from recognizing cancer cells.

PD-L1 and CPS

PD-L1 is a protein that helps the tumor evade the immune system; CPS (combined positive score) is a score measuring PD-L1 expression on tumor and immune cells.

Progression-free survival

The time after the start of treatment during which the disease does not grow and there is no loss of life.

Overall survival

The length of time a patient lives after the start of treatment; the most important measure in metastatic disease.

Hazard ratio (HR)

The ratio of event rates in two groups; a value below 1 favors the new treatment, and a value close to 1 indicates no difference.

CDK4/6 inhibitor

Oral drugs that slow cell division, used together with endocrine therapy in hormone receptor-positive breast cancer (palbociclib, ribociclib, abemaciclib).