Keytruda Plus Xgeva Shrank Tumors in 31% of Patients With Clear Cell Kidney Cancer

Xgeva (denosumab), a drug that blocks a bone-signaling protein called RANKL, shrank tumors in 31% of patients with advanced clear cell renal cell carcinoma when added to the immunotherapy Keytruda (pembrolizumab) in the phase 2 KEYPAD trial.

Clear cell renal cell carcinoma is the most common form of kidney cancer. All 59 participants were treated at one of 16 sites across Australia, and all had cancer that had spread or could not be removed with surgery and had grown during or after treatment with a VEGFR-targeted tyrosine kinase inhibitor, a targeted therapy pill that blocks blood vessels tumors need to grow.

The trial tested whether blocking RANKL could make Keytruda work better in patients whose cancer had already grown after another treatment. Researchers were looking for a tumor response rate of at least 40% before considering the approach for further study.

How well did Keytruda plus Xgeva work in the phase 2 KEYPAD kidney cancer trial?

Tumors shrank in 18 of the 58 patients who could be evaluated for treatment response (31%). This was the main measure researchers used to determine whether the treatment was working.

The result was below the 40% response rate researchers had set before the trial began as the level that would justify further study.

Every response was partial, meaning tumors became smaller but did not disappear completely. No patient had a complete response. Cancer stopped growing but did not shrink in 15 patients (26%), while it continued to grow in 24 patients (41%).

Among patients whose tumors shrank, the response lasted a median of 17 months. The median time until a response was seen was 2.7 months.

Patients lived a median of 7.5 months without their cancer growing or spreading. At 6 months, 53% of patients had not experienced cancer growth. When researchers combined patients, whose tumors shrank with those whose cancer remained stable, 57% had disease control at 6 months (33 of 58 patients).

Among the 24 patients whose cancer had spread to the bones, 7 had tumors that shrank (29%) and 5 had cancer that remained stable (21%). The researchers did not find meaningful differences in treatment effectiveness or safety between patients with and without cancer that had spread to the bones.

The combination was "safe in pretreated clear cell renal [kidney] carcinoma, with activity meriting further investigation," concluded the study authors, led by Dr. Carole A. Harris of the Department of Medical Oncology at St George Hospital.

The 53% of patients who had not experienced cancer growth at 6 months and the median 7.5 months without cancer growth compared favorably with results from other trials involving patients with similar treatment histories. Those studies reported 6-month rates of 30% to 46% and median times without cancer growth of 2.7 to 5.6 months. These comparisons came from previously published trials cited in the paper, not from a direct comparison with KEYPAD.

Who was in the phase 2 KEYPAD trial of Keytruda and Xgeva for clear cell kidney cancer?

KEYPAD, also known as ANZUP 1601, was a single-arm trial, meaning everyone received the same treatment and there was no group receiving a different treatment or placebo for comparison.

Fifty-nine people enrolled at 16 Australian sites between December 2017 and July 2022. The Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group sponsored the trial. Merck Sharp and Dohme (Australia) Pty Ltd and Amgen supplied the drugs and funding without direct input into how the trial ran or how the results were analyzed.

Participants were 18 or older and had clear cell kidney cancer that could not be removed with surgery or had spread to other parts of the body. Their cancer also had to have grown during or after treatment with a VEGFR-targeted pill.

People who had previously received Xgeva or an immune checkpoint inhibitor were excluded, as were people with untreated brain metastases or active autoimmune disease treated in the previous 2 years.

Keytruda was given at 200 mg through a vein every 3 weeks. Xgeva was given at 120 mg as an injection under the skin on days 1, 8 and 22, then every 3 weeks. Treatment continued until the cancer grew or side effects became unacceptable, up to a maximum of 24 months.

Patients received treatment for a median of 8.1 months and were followed for a median of 40 months. Treatment stopped because the cancer grew in 34 patients (58%), because of side effects in 13 patients (22%), after completing 2 years of treatment in 4 patients (7%) and at a clinician's preference in 3 patients (5%).

What side effects occurred with Keytruda and Xgeva in the KEYPAD kidney cancer trial?

Side effects of any severity occurred in 58 of 59 participants (98%), and most were mild or moderate. The most common were fatigue (53%), pain (29%) and rash (27%). More severe grade 3 or 4 side effects occurred in 38 participants (64%).

The most common severe treatment-related side effects were elevated lipase, a digestive enzyme measured in blood tests (14%); colitis, or inflammation of the colon (7%); lung infections (7%); and high blood sugar (7%).

Immune-related side effects, which can happen when immunotherapy causes the immune system to attack healthy tissue, occurred in 19 participants (32%). More severe immune-related side effects occurred in 12 participants (21%).

The most clinically significant immune-related side effects included pneumonitis, or inflammation of the lungs, in 6 participants; myocarditis, or inflammation of the heart muscle, in 3 participants; and colitis in 3 participants.

Serious side effects were reported in 40 participants (68%), most often infections (17%) and heart disorders (12%). Side effects attributed to Keytruda occurred in 17 participants and included one death.

Two participants had side effects attributed to Xgeva. One had grade 3 hypocalcemia, or low blood calcium, and one had grade 3 osteonecrosis of the jaw, a condition in which jawbone tissue breaks down.

Three participants died during the trial, including one death from myositis, or muscle inflammation, that was attributed to the study treatment.

Ten skeletal-related events, or bone complications, occurred. A quarter of participants had experienced a first bone complication by 37 months. Researchers could not calculate the median time to a first bone complication because too few events occurred.

What happens next with Keytruda and Xgeva for clear cell kidney cancer?

KEYPAD is the first trial to combine a PD-1-targeted immunotherapy with a treatment that blocks RANKL in kidney cancer. The researchers did not identify any new safety concerns compared with what has previously been reported for either drug alone.

However, the researchers cautioned that the results should not be directly compared with other trials because KEYPAD did not include a comparison group. Side effects were also assessed by investigators rather than patients, and the study did not collect information directly from patients about their symptoms or quality of life.

The study also did not collect overall survival data or information about treatments patients received after leaving the trial.

Researchers are continuing laboratory studies of blood and tissue samples collected during KEYPAD to look for clues about which patients may benefit most from adding Xgeva to Keytruda. The authors said the results support further clinical trials to determine whether blocking RANKL can improve immunotherapy outcomes in kidney cancer.

References

1. Harris CA, et al. "Pembrolizumab and Denosumab in Clear-Cell Renal-Cell Carcinoma." Clinical Genitourinary Cancer. Published May 27, 2026.

For more news on cancer updates, research and education, don’t forget to subscribe to CURE®’s newsletters here.