GU cancer

Avelumab the new first line standard of care for advanced UC

Adding the checkpoint inhibitor avelumab to best supportive care (BSC) following induction chemotherapy for advanced urothelial carcinoma (UC) significantly improved overall survival (OS) compared with BSC alone, according to findings from the phase 3 JAVELIN Bladder 100 trial.

The study, presented during the ASCO20 Virtual Scientific Program has been labelled ‘practice changing’ and according to investigators the findings signal ‘a new first-line standard of care’ for advanced UC.

Presenting the data, lead investigator and director of the Barts Cancer Institute in the UK, Professor Thomas Powels, said immune checkpoint inhibitors are standard second line treatment in urothelial cancer for patients with disease progression after chemotherapy – which will occur in most patients because chemotherapy resistance occurs quickly in UC.

Despite this, only a minority of patients achieve long-term durable remissions with second line treatment – underscoring a need for additional treatment options, he says.

JAVELIN Bladder 100, conducted across multiple sites around the world including 16 sites in Australia, provides the first data demonstrating the efficacy of avelumab as a first-line treatment in the maintenance setting before disease progression.

The trial included 700 patients with unresectable locally advanced or metastatic urothelial carcinoma who had no disease progression following chemotherapy (gemcitabine with either cisplatin or carboplatin).

Investigators randomly assigned 350 patients to receive BSC alone and 350 to receive avelumab plus BSC. The groups had a median follow-up period of 19.2 and 19.6 months, respectively.

Of the 700 patients, 358 (51%) had PD-L1–positive tumours.

The results showed that the addition of the PD-L1 inhibitor reduced the risk of death by 31%. The median overall survival (OS) was 21.4 months with avelumab plus BSC compared with 14.3 months with BSC alone (HR, 0.69; 95% CI, 0.56-0.86; P <o.001).

The survival benefit with avelumab was seen across all prespecified subgroups, including those defined by cisplatin-based or carboplatin-based chemotherapy, and regardless of whether response or stable disease was reached after first-line induction chemotherapy.

First breakthrough in 30 years

In an interview with the limbic, investigator of the Australian arm of the trial Professor Howard Gurney, Director of Clinical Trials for the Faculty of Medicine and Health Sciences at Macquarie University, described JAVELIN 100 as one of the biggest UC breakthroughs in three decades.

“Chemotherapy works, for a short while, but there have been no advances from chemotherapy for 30 years and until recently it’s been very hard to improve on chemotherapy no matter what combination of drugs we gave,” he said.

“Apart from giving the immunotherapy pembrolizumab in the second line setting very few urothelial bladder cancer studies give a survival advantage,” he added, noting that the chemotherapy he gives today is almost identical to the chemotherapy he had been giving for UC as a trainee registrar.

“But this study is different – we’re giving chemotherapy like we normally do and then we’re selecting patients who respond, whose disease hasn’t progressed on chemotherapy and giving them immunotherapy within four to 10 weeks of finishing chemotherapy. Doing that gives an impressive survival advantage, you can see on the curves there’s a big gap between the people who did not receive the immunotherapy and the ones who did.

“If you just look at how many people are alive at 18 months on the immunotherapy it was 60% versus 44% – that’s a big difference in urothelial cancer.”

Professor Gurney says while earlier immunotherapy is becoming the standard of care across a number of cancers, chemotherapy is still very important in UC.

“Of course you think if the immunotherapy works in the second line setting let’s just give it at the same time as chemotherapy. We’ve done four studies in that setting and so far our early results say it’s no better than giving chemotherapy alone. So far, it’s in this first line maintenance setting that immunotherapy works – in a sense you’re using the response to chemotherapy to select out patients.”

However Professor Gurney says it important to remember that even in this situation where the results are quite striking, there are still 40% of the patients on the immunotherapy who will progress very rapidly.

“In other words it [does] absolutely nothing – so there’s still a long way to go to improve the situation, but this is one of the biggest breakthroughs in 30 years. The first big breakthrough was pembrolizumab about four years ago and this is the next big thing.”

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