Induction Yervoy and Opdivo May Support Bladder Preservation

Induction Yervoy (ipilimumab) plus Opdivo (nivolumab) followed by consolidative chemoradiotherapy demonstrated bladder preservation outcomes in patients with stage 2/3 urothelial carcinoma of the bladder, meeting the primary end point of the phase 2 INDIBLADE trial, according to data presented at the American Society of Clinical Oncology Genitourinary Cancers Symposium.

At a median follow-up of 28.7 months, the estimated 2-year bladder-intact event-free survival rate was 78%. The 2-year overall survival rate reached 96%. Investigators also reported that post-induction circulating tumor DNA positivity was associated with inferior bladder-intact event-free survival, supporting a potential role for circulating tumor DNA–guided treatment selection.

“Potent induction combination immunotherapy followed by consolidated chemoradiotherapy is an effective bladder-sparing treatment for a broad population of patients with muscle-invasive bladder cancer,” lead presenter Jan-Jaap J. Mellema of the Netherlands Cancer Institute in Amsterdam said during the meeting. “Absence of circulating tumor DNA after immunotherapy was associated with bladder-intact event-free survival and could aid clinical decision making after systemic induction.”

Nine bladder-intact event-free survival events were observed, yielding the 78% 2-year rate. Overall survival data remain immature but favorable, with 3 deaths reported at the time of analysis.

Baseline circulating tumor DNA status was not significantly associated with bladder-intact event-free survival. However, patients who were circulating tumor DNA positive after induction experienced substantially higher event risk compared with those who were circulating tumor DNA negative.

Mellema noted that patients who experienced disease progression tended to remain circulating tumor DNA positive throughout treatment or convert to positivity at the time of recurrence. Those without events were typically circulating tumor DNA negative at baseline or achieved clearance during induction.

INDIBLADE trial design and patient population

INDIBLADE was an investigator-initiated single-arm multicenter phase 2 study conducted in the Netherlands. Eligible patients had clinical T2 to T4aN0 to 2M0 muscle-invasive urothelial carcinoma with lymph nodes amenable to radiation and an Eastern Cooperative Oncology Group performance status of 0 or 1. Prior pelvic radiotherapy prior systemic therapy for muscle-invasive disease extensive carcinoma in situ upper tract urothelial carcinoma and bilateral hydronephrosis were exclusion criteria.

Patients received induction Yervoy plus Opdivo for 2 cycles followed by Opdivo for 1 cycle. Response assessment incorporated imaging and cystoscopy. In the absence of progression patients proceeded to chemoradiotherapy consisting of radiotherapy with concurrent mitomycin C and fluorouracil or capecitabine.

The primary end point was 2-year bladder-intact event-free survival. Secondary end points included overall survival safety and circulating tumor DNA analyses.

Baseline characteristics reflected a higher-risk population: 42% had clinical T3 disease and 14% had node-positive involvement. Median age was 65 years.

Most patients completed planned induction therapy although a minority did not receive all cycles. Five patients did not proceed to chemoradiotherapy including 4 due to disease progression and 1 by patient choice. Overall 45 of 50 patients initiated chemoradiotherapy.

Safety profile

No new safety signals were observed. Chemoradiotherapy-related side effects occurred in 71% of patients with grade 3 or 4 events in 7%. Immunotherapy-related side effects were reported in 94% of patients with grade 3 or 4 events in 24%.

Common immune-related toxicities included fatigue maculopapular rash diarrhea pruritus colitis hypothyroidism pneumonitis hypophysitis and adrenal insufficiency. A single colon perforation was reported. Chemoradiotherapy-related toxicities included urinary frequency dysuria anemia and noninfectious cystitis predominantly low grade.

Circulating tumor DNA as a potential decision-making tool

Serial plasma circulating tumor DNA was collected before each induction cycle at response assessments and during follow-up. Of patients without bladder-intact event-free survival events 26 were circulating tumor DNA negative at baseline and remained undetectable throughout therapy.

Post-induction circulating tumor DNA status demonstrated prognostic separation. Patients who were circulating tumor DNA positive after immunotherapy experienced worse bladder-intact event-free survival compared with those who were circulating tumor DNA negative supporting circulating tumor DNA as a potential biomarker for selecting candidates for bladder preservation versus early cystectomy.

Clinical implications

The investigators concluded that induction dual checkpoint blockade followed by chemoradiotherapy is a feasible and active bladder-sparing strategy in muscle-invasive disease including patients with higher-risk features such as T3 tumors and nodal involvement amenable to radiation. Longer follow-up will be needed to assess durability of bladder preservation and late toxicities.

References

1. “Induction ipilimumab plus nivolumab followed by consolidating chemoradiotherapy as bladder-sparing treatment in stage II/III urothelial carcinoma of the bladder: The phase 2 Indi-Blade trial,” by Jan-Jaap J. Mellema. The Journal of Clinical Oncology.

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