LAS VEGAS — Event-free survival (EFS) in high-risk non-muscle invasive bladder cancer (NMIBC) improved significantly when patients received the PD-1 inhibitor sasanlimab in addition to bacillus Calmette-Guérin (BCG), a randomized trial showed.

The 3-year EFS increased from 74.8% with standard-of-care BCG induction and maintenance to 82.1% with the addition of sasanlimab. Most of the improvement in the composite endpoint of EFS resulted from a greater than 50% reduction in the risk of high-grade recurrence (7.4% vs 15.1%). The superiority of the combination remained consistent across a prespecified subgroup analysis.

A secondary analysis showed that combination induction therapy without maintenance did not improve survival as compared with BCG induction and maintenance, reported Neal D. Shore, MD, of Carolina Urologic Research Center in Myrtle Beach, South Carolina, here at the American Urological Association (AUA) meeting.

“There are three other large trials looking at checkpoint blockade in BCG-naive patients, and this is the first one reported, showing a statistically significant prolongation of EFS with sasanlimab in combination with BCG. In patients with CIS [carcinoma in situ], the probability of continued CR [complete response] was greater with the combination, 92% versus 68%, at 36 months. The safety profile was as expected.”

“I think it is important to recognize the unique subcutaneous administration [of sasanlimab], and that we will need continued collaborative, multidisciplinary efforts to make sure we optimize shared decision making for patients who are at risk.”

Open to Interpretation

The results, though positive, will be open to different interpretations by different observers, said Peter Black, MD, of Vancouver General Hospital and the University of British Columbia.

“The results appear to show a real benefit with respect to recurrence of the bladder cancer, but progression to muscle invasive bladder cancer is the most important outcome, and we do not yet see a difference there — and we would not expect to — the trial was not designed to detect that difference, especially after relatively short follow-up,” Black told MedPage Today.

Grade 3/4 adverse events occurred almost five times as often in the combination arm, he added, and combining sasanlimab to BCG will significantly increase the cost of treatment.

“I think it is likely that the drug will be approved by the FDA for this indication and it will come down to a discussion with the individual patient to determine if he/she wants to assume the risk of additional toxicity for a modest EFS benefit,” said Black. “We would of course like some kind of clinical marker or biomarker to guide this sort of decision. The report at the AUA suggested that patients with CIS may benefit especially with respect to durability of response.”

As Shore noted, three other ongoing trials are evaluating anti-PD-1 agents in combination with BCG for NMIBC.

“I would assume that this is a class effect,” said Black. “We will see if there are differences in outcomes, but those are just as likely to be due to differences in trial design.”

Background, Key Findings

Standard of care for high-risk NMIBC is transurethral resection of the bladder tumor followed by induction therapy with BCG and then maintenance BCG, Shore noted in his introduction. About 40% of patients have recurrent or progressive disease within 24 months, which is associated with an unfavorable prognosis.

Several studies have shown increased PD-1 expression in bladder tumors after BCG treatment, supporting combination treatment with a PD(L)1 inhibitor. Sasanlimab demonstrated durable anti-tumor activity and a manageable safety profile in studies involving patients with advanced or metastatic solid tumors, said Shore.

Investigators in the multicenter phase III CREST trial randomized patients with high risk NMIBC and no prior exposure to BCG to three treatment arms: sasanlimab plus BCG induction and maintenance, sasanlimab plus BCG induction only, or BCG induction and maintenance. The primary endpoint was EFS for the comparison of BCG induction and maintenance with or without sasanlimab. Shore reported findings only for that comparison. EFS comprised high-grade recurrence, progressive disease, CIS persistence, and death from any cause.

The study population comprised 1,055 patients, 703 randomized to BCG ± the PD-1 inhibitor. A majority of the patients (55-58.0%) had stage T1 disease, followed by Ta (27-30%), CIS plus Ta or T1 (25.0%), and pure CIS (14-15%). Pathology results showed that ~10% of patients had low-grade tumors, and all the rest had high-grade disease.

After a median follow-up of 36.3 months, the data showed that the addition of sasanlimab to BCG was associated with a 32% reduction in the EFS hazard (95% CI 0.49-0.94, P=0.0095). The 24-month landmark analysis showed a separation of survival curves favoring the combination (84.7% vs 79.9%), and the difference increased during the additional 12 months of follow-up.

Beyond the difference in high-grade recurrence, the two treatment strategies had similar effects on progression to locally advanced/metastatic disease (three patients with the combination vs seven for BCG alone), progression-to muscle-invasive disease (seven in each arm), and stage progression (seven in each arm).

The secondary endpoint of investigator-assessed overall survival did not differ between treatment arms after a median follow-up of 40.9 months (90.9% with the combination vs 91.7%).

The CR rates were 89.8% with sasanlimab and 85.2% with BCG only. However, 91.7% of CRs in the sasanlimab arm were ongoing at 36 months as compared with 67.7% in the BCG-only group.

Treatment-related adverse events (TRAEs) occurred in 58% of the sasanlimab arm and 63.9% of the BCG arm. However, rates of grade 3/4 TRAEs were 29.1% with sasanlimab versus 6.3% with BCG alone. The most common grade 3/4 TRAEs associated with the PD-1 inhibitor were increased lipase (6.0%), hematuria (4.0%), increased amylase (2.3%), and increased liver enzymes (2.3% each for alanine aminotransferase and aspartate aminotransferase).

Grade 3/4 immune-mediated AEs occurred in 15.8% of the sasanlimab arm, most commonly hepatitis (3.4%), rash (2.9%), and pancreatitis (2.0%).

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