The anticipated approval of the highly effective EV-Pembro combination in the perioperative setting will create a new clinical challenge. When these patients eventually relapse years later, clinicians will face a dilemma: re-challenge with the same potent regimen that worked before or switch to older, likely less effective chemotherapies.
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The emergence of positive data from trials like PATINA creates a dilemma for oncologists treating patients who are already stable on an older maintenance therapy. The consensus suggests not altering a successful regimen to avoid disrupting patient stability, revealing a cautious approach to integrating new evidence into established care.
Unlike immunotherapy, where re-challenge after progression is dubious, there is an emerging clinical practice of re-challenging patients with the same antibody-drug conjugate (ADC), such as enfortumab vedotin (EV), after a treatment break forced by toxicity. Anecdotally, patients are showing great responses, highlighting a key area for prospective data generation.
Real-world data suggests that using one antibody-drug conjugate (ADC) immediately after another is often ineffective. A potential strategy to overcome this resistance is to administer a different class of chemotherapy before starting the second ADC.
When a highly effective therapy like EV Pembro was approved for 'cisplatin ineligible' patients, the definition of 'ineligible' became very elastic in practice. This demonstrates that when a new treatment is seen as transformative, clinicians find ways to qualify patients, putting pressure on established guidelines.
Experts question the efficacy of sequencing ADCs like EV (Nectin-4 target) and DV (HER2 target) because they share the same MMAE chemo payload. Since resistance is often tied to the payload, not the target antibody, switching targets may not overcome resistance, though anecdotal responses have been observed.
In metastatic breast cancer, approximately one-third of patients are unable to proceed to a second line of therapy due to disease progression or declining performance status. This high attrition rate argues for using the most effective agents, such as ADCs, in the first-line setting.
Rather than moving through distinct lines of therapy, a future strategy could involve an "ADC switch." When a patient progresses on an ADC-IO combination, the IO backbone would remain while the ADC is swapped for one with a different, non-cross-resistant mechanism, adapting the treatment in real-time.
Emerging data shows that a second ADC, particularly one with the same payload, often has limited efficacy. This suggests clinicians must be highly strategic in selecting the first ADC, as it may be their most impactful opportunity for this class of drugs.
Perioperative enfortumab vedotin-pembrolizumab (EV-Pembro) is surprisingly well-tolerated on a per-cycle basis compared to the traditional GEMSYS chemotherapy regimen. This challenges preconceived notions about the toxicity of this powerful combination, though cumulative toxicity over longer durations remains a key factor.
With pathologic complete response rates approaching 67% in patients completing neoadjuvant EV-Pembro, a majority of cystectomies are now removing cancer-free bladders. This creates an ethical and clinical imperative to rapidly launch prospective trials to validate bladder preservation strategies and avoid overtreatment.