Keytruda (pembrolizumab) is one of the most significant treatments to emerge for bladder cancer in the past decade, but its effectiveness varies considerably depending on the stage of disease and whether it’s used alone or with another drug. In advanced bladder cancer that has spread or can’t be surgically removed, Keytruda combined with another targeted therapy is now the single preferred first-line treatment in national oncology guidelines. Used alone in earlier-stage disease, the results are more modest.
Advanced Bladder Cancer: Keytruda Alone
For patients whose bladder cancer has returned or spread after initial chemotherapy, Keytruda on its own extends survival compared to a second round of chemotherapy. In the landmark KEYNOTE-045 trial, patients treated with Keytruda lived a median of 10.1 months, compared to 7.2 months for those receiving chemotherapy. That’s roughly a three-month survival advantage, with a 29% reduction in the risk of death.
The response rate tells a similar story. About 22% of patients saw their tumors shrink meaningfully on Keytruda, compared to 11% on chemotherapy. That means roughly one in five patients responds, which is a meaningful improvement over chemo but also means the majority of patients don’t see tumor shrinkage. The five-year follow-up data from this trial confirmed the benefit held up over time, and those who did respond often had durable responses lasting well beyond what chemotherapy typically delivers.
The Combination That Changed First-Line Treatment
The real game-changer for advanced bladder cancer came when Keytruda was paired with enfortumab vedotin (sold as Padcev), an antibody-drug conjugate that delivers chemotherapy directly to cancer cells. The FDA approved this combination in December 2023 for patients with locally advanced or metastatic urothelial cancer, and it quickly reshaped treatment guidelines.
The National Comprehensive Cancer Network now lists this combination as the only preferred first-line regimen for metastatic bladder cancer, regardless of whether patients can tolerate cisplatin-based chemotherapy. That’s a striking distinction. Previously, different patients were funneled into different treatment tracks based on their ability to handle cisplatin. Now, Keytruda plus enfortumab vedotin is the top recommendation for everyone. Real-world data from multiple cancer centers shows a median progression-free survival of roughly 10 to 13 months with this combination, depending on the patient population studied.
This approval represented a shift from accelerated approval (granted earlier for patients who couldn’t receive cisplatin) to full approval for all eligible patients with advanced disease, reflecting stronger and more complete clinical evidence.
Non-Muscle Invasive Bladder Cancer
Keytruda also has a role in earlier-stage bladder cancer that hasn’t grown into the muscle wall of the bladder. This type, called non-muscle invasive bladder cancer, is usually treated first with BCG, a therapy delivered directly into the bladder. But some patients stop responding to BCG, and their main alternative has traditionally been surgical removal of the entire bladder.
For these BCG-unresponsive patients, Keytruda offers a bladder-sparing option, though expectations should be calibrated. In the KEYNOTE-057 trial, 41% of patients with carcinoma in situ (a flat, high-grade form of the disease) achieved a complete response at three months. For patients with papillary tumors without carcinoma in situ, about 44% remained free of high-risk disease at one year, with a median disease-free survival of roughly 8 months.
These numbers reflect a treatment that works well for a meaningful portion of patients but doesn’t work for everyone. Current guidelines list Keytruda as an option for select patients with BCG-unresponsive high-risk disease, particularly those who want to avoid or delay bladder removal surgery.
What Predicts a Good Response
Not every patient’s bladder cancer responds equally to Keytruda, and researchers have identified biological markers that help predict who benefits most. The key marker is called PD-L1 expression, a measure of how much of a specific protein appears on and around tumor cells. Pathologists calculate a Combined Positive Score (CPS) by counting the PD-L1-expressing cells relative to total tumor cells.
Patients with high PD-L1 expression (a CPS of 10 or higher) consistently show better outcomes. In studies of similar immune checkpoint inhibitors, patients with high expression scores had response rates roughly two to three times higher than those with low scores. For patients with low PD-L1 expression, Keytruda alone performs no better than standard chemotherapy, which is one reason the combination approach with enfortumab vedotin has become so important: it appears to benefit patients regardless of their PD-L1 status.
Your oncologist will typically order PD-L1 testing on a biopsy sample before recommending Keytruda as a standalone treatment. This result helps guide whether immunotherapy alone, combination therapy, or chemotherapy makes the most sense for your specific cancer.
Side Effects and Tolerability
Keytruda works by releasing the brakes on your immune system, which means side effects stem from the immune system attacking healthy tissue rather than from the direct cell-killing effects of chemotherapy. In bladder cancer trials, serious (grade 3 or 4) side effects from treatment occurred in about 14% of patients. The most common serious reactions were colitis and diarrhea, each affecting roughly 2% of patients.
About 11% of patients discontinued Keytruda due to side effects. That’s notably lower than discontinuation rates typically seen with platinum-based chemotherapy regimens, which is one reason Keytruda has been particularly valuable for older patients or those with kidney problems who can’t tolerate traditional chemo. Common lower-grade side effects include fatigue, itching, rash, and joint pain. Most immune-related reactions are manageable when caught early but can become serious if ignored, so treatment involves regular monitoring through blood tests and symptom check-ins.
What Treatment Looks Like
Keytruda is given as an intravenous infusion, typically every three weeks at a flat dose. Each infusion takes about 30 minutes once you’re settled in the infusion chair, though plan for a longer visit when accounting for check-in, vitals, and post-infusion observation. Treatment continues on this schedule for up to two years, as long as the cancer isn’t progressing and side effects remain tolerable. Some patients on the combination regimen with enfortumab vedotin may receive Keytruda on an every-six-week schedule instead, with the partner drug given more frequently.
Unlike chemotherapy, which is given for a set number of cycles, Keytruda treatment is open-ended within that two-year window. If the cancer responds and remains controlled, you stay on treatment. If it progresses, your oncologist will reassess options. Some patients who complete the full two years and later experience cancer progression may be considered for retreatment.