Comparison of enfortumab vedotin (EV, aka Padcev) and pembrolizumab (Keytruda) in metastatic urothelial/bladder cancer

What we know of their benefits, limitations, and toxicities.

Mechanisms & therapeutic role (in metastatic bladder cancer)

Enfortumab vedotin (EV)

• EV is an antibody-drug conjugate (ADC) targeting nectin-4 (a cell-surface adhesion molecule expressed in urothelial carcinoma). The antibody binds nectin-4, is internalized, and releases a cytotoxic payload (monomethyl auristatin E, MMAE) inside the cancer cell, disrupting microtubules and causing cell death.
• It is approved for patients with advanced/metastatic urothelial carcinoma (UC) who have received prior therapy (typically platinum chemo + immune checkpoint inhibitors) and have disease progression.
• In trials, EV as monotherapy has shown an objective response rate (ORR) in the range of ~ 40-45 % (including a small percent of complete responses), with median progression-free survival (PFS) ~5–6 months and median overall survival (OS) ~11–12 months in heavily pretreated populations.
• In the EV-301 phase III trial (EV vs chemotherapy in previously treated patients), the rates of treatment-related adverse events (AEs) and high-grade AEs were similar to chemo, but the toxicity patterns differ.
• More recently, combination of EV + pembrolizumab in first-line (untreated metastatic UC) is being studied. In early results, the combo yielded superior outcomes versus chemotherapy.
• In the KEYNOTE-A39 (EV + pembrolizumab) combination setting, notable improvements in event-free survival and OS have been reported.
• According to NCCN-oriented sources, EV + pembrolizumab nearly doubled median OS vs chemotherapy (e.g. ~31.5 vs ~16.1 months) and also improved PFS and ORR in la/mUC (locally advanced or metastatic UC) settings.
• In a press summary (NIH cancer blog), the combination led to tumor shrinkage or stabilization in ~67 % of patients vs ~44 % with chemo; complete responses in ~30 % vs ~12 %.

Limitation / caveats:

• The benefit is more modest in patients heavily pretreated or with resistant disease; after EV failure, further options are limited.
• Response durability is variable; many responders eventually progress.

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Pembrolizumab (immune checkpoint inhibitor)

• Pembrolizumab is a monoclonal antibody blocking PD-1 on T-cells, releasing “brakes” on immune response to allow T-cells to attack tumor cells.
• In urothelial carcinoma, pembrolizumab has been used in second-line or later settings (after platinum chemotherapy) with durable responses in a subset of patients.
• In the KEYNOTE-045 trial (pembrolizumab vs chemotherapy in advanced UC after platinum), pembrolizumab improved overall survival (median OS ~10.3 vs ~7.4 months) with a more favorable safety profile.
• Immune checkpoint inhibitors (ICI) like pembrolizumab have the advantage of durable responses in a minority of patients (i.e. “tail of curve” benefit).
• Pembrolizumab is useful even in patients unfit for cisplatin or as subsequent lines depending on PD-L1 status and prior treatments.

Limitations:

• Only a subset of patients derive benefit; many do not respond.
• Immune-related adverse events (irAEs) can be serious.
• If patients have aggressive, bulky, rapidly progressing disease, ICIs may not act fast enough.

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Side effects / adverse event profiles

Because combining EV + pembrolizumab is under study and being used increasingly, I’ll list both monotherapy profiles and what is known about the combo.

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EV (monotherapy) toxicities

Common (≥20 %) adverse events:

• Fatigue
• Peripheral neuropathy (sensory)
• Decreased appetite
• Rash / dermatologic toxicities
• Alopecia (hair loss)
• Nausea
• Diarrhea
• Dysgeusia (altered taste)
• Dry eye, pruritus, dry skin
• Ocular disorders: ~46 % of treated patients had eye/ocular events (keratitis, blurred vision, limbal stem cell deficiency, etc.)

Grade ≥ 3 / serious AEs / special concerns:

• Skin reactions / rash (e.g. maculopapular, severe dermatologic events)
• Hyperglycemia (high blood sugar) (in some patients)
• Peripheral neuropathy severe forms leading to dose modifications or discontinuation (in trials ~6 % discontinuation)
• Treatment-related skin reactions (in EV-301 trial ~47.3 %) and hyperglycemia (~6.8 %) were more common versus chemo.
• Laboratory abnormalities: lymphopenia, low hemoglobin, hypophosphatemia, elevated lipase, sodium decrease, glucose increase, urate increase
• Risk of extravasation (leakage of drug out of vein) with local tissue damage
• Pulmonary toxicity / lung events (rare)

In EV-301, grade ≥3 AEs occurred in ~52.4 % of patients receiving EV. 

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Pembrolizumab (monotherapy / in UC) toxicities

Common (all grades):

• Fatigue
• Rash / pruritus
• Diarrhea
• Nausea
• Decreased appetite
• Musculoskeletal pain
• Cough, dyspnea
• Endocrine dysfunction (e.g. thyroid disorders)
• Itching, skin reactions
• Others: constipation, joint pain, GI disturbances, low thyroid hormone levels

Serious / immune-related adverse events (irAEs):

• Pneumonitis
• Colitis
• Hepatitis
• Nephritis
• Endocrinopathies (thyroiditis, hypophysitis, adrenal insufficiency)
• Rare but life-threatening: severe pneumonia, severe colitis, adrenal crisis, severe skin reactions
• Overall, serious adverse events occur in ~40 % of pembrolizumab-treated UC patients (in some trials)
• Discontinuation due to AEs has been ~8-11 % in various UC trials

Immune-mediated AEs are managed per guidelines (steroids, holding drug, etc.). 

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EV + Pembrolizumab combination (emerging data)

Because combining a cytotoxic ADC plus immunotherapy may lead to overlapping or synergistic toxicities, we must watch for:

• In studies, the most frequent treatment-emergent AEs of EV + pembrolizumab included rash, peripheral neuropathy, fatigue, pruritus, diarrhea, alopecia, weight loss, decreased appetite, dry eye, urinary tract infection.
• Grade 3–4 AEs in the combo: rash (~15 %), peripheral neuropathy (~8 %), fatigue (~6 %) in reported trials.
• Fatal AEs: ~3.9 % of patients in one combo trial; of those, ~0.9 % were considered treatment-related (causes included multiple organ dysfunction, immune-mediated lung disease, diarrhea, asthenia)
• In KEYNOTE-A39, fatal adverse reactions in ~3.9 % (e.g. acute respiratory failure, pneumonia, interstitial lung disease) and serious AEs in ~50 %. Permanent discontinuation of pembrolizumab was ~27 %.
• Skin reactions, pneumonitis, diarrhea are overlapping AE domains (both agents can cause these), complicating attribution.

Thus, the combination raises risk of enhanced dermatologic toxicity, neuropathy, immune-mediated organ toxicity, and additive general side effects (fatigue, GI symptoms).

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Benefit vs risk trade-off & clinical considerations

• The combination of EV + pembrolizumab shows promise in improving ORR, PFS, and OS over chemotherapy in first-line la/mUC, potentially shifting treatment paradigms.
• But the combo brings a higher burden of toxicity and needs careful monitoring. Patients with comorbidities, baseline neuropathy, poor functional reserve, or prior autoimmune disease may be less ideal candidates.
• Dose modifications, interruptions, or discontinuations are relatively common in EV trials for peripheral neuropathy and rash.
• For pembrolizumab, a key strength is the possibility of durable responses (immune “tail”), but the unpredictability of who will benefit means patient selection biomarkers (PD-L1 status, TMB, etc.) and close monitoring of irAEs are crucial.

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