A panel of experts reviews key clinical trial data supporting use of maintenance therapy in metastatic urothelial carcinoma.
Petros Grivas, MD, PhD: Srikala, can you briefly summarize the JAVELIN Bladder 100 trial for the audience?
Srikala Sridhar, MD, MSc, FRCPC: This was about a 700-patient study. Patients were randomized 1:1 to receive avelumab or best supportive care. The avelumab was given at a dose of 10 mg/kg every 2 weeks. And as we mentioned earlier, patients were those who’d had either gemcitabine and cisplatin or gemcitabine and carboplatin. They had to have had between 4 and 6 cycles and had to have evidence of disease control. By that I mean stable disease, partial response, or complete response. Then they were treated after a treatment-free interval of between 4 and 10 weeks, and that’s when the randomization occurred. The primary end point was overall survival in the intention-to-treat population and in the PD-L1–high population. We’ve heard already the results, that there was an improvement in overall survival, 21 vs about 14 months, about a 6-month improvement. It’s probably one of the first and largest positive phase 3 studies in the frontline setting.
Petros Grivas, MD, PhD: Itotally agree with you, and the hazard ratio, to Cora’s point, held up at 0.76 with longer follow-up despite that about three-quarters of the patients got subsequent therapy in the control arm, substantiating the benefit you pointed out. I think, Cora, you mentioned before in the design of the study, you had avelumab until progression or unacceptable toxicity. You kept going. So, patients are asking, “Am I getting avelumab every 2 weeks forever?” They said it would be great if you keep doing well, no progression, that would be great. But Guru, do you ever use anything different, or do you stick with level 1 evidence with avelumab? Do you use pembrolizumab? What is your practice?
Guru P. Sonpavde, MD: I stick with avelumab in general because that’s the phase 3 trial that has shown the improvement in survival. The other trial that’s been done with a checkpoint inhibitor is with pembrolizumab. That was a smaller, randomized phase 2 trial of around 50 patients per arm. It had a primary end point of PFS, progression-free survival, which was prolonged. It was not powered for survival. That has been shown in a phase 2 trial, so I don’t consider that standard in the switch-maintenance setting.
Petros Grivas, MD, PhD: I agree with you, and I try to stick with level 1 evidence with avelumab. Some other data came about recently in 2022, we saw data from the ATLANTIS trial, with maintenance rucaparib, and maintenance cabozantinib. Do you want to briefly comment on this data set we saw recently?
Guru P. Sonpavde, MD: ATLANTIS is a randomized phase 2 trial. It’s a platform trial going on in the United Kingdom that is in the switch-maintenance setting in patients who have stable or responding disease post platinum-based chemotherapy. Within each molecular cohort, there is a further randomization to placebo or drug X. They had an arm with DNA damage repair alterations where they gave rucaparib vs placebo. And they had an arm without an alteration that was of interest. In that, they gave cabozantinib vs placebo. They have a third arm that hasn’t been reported yet that is looking at enzalutamide, that is in patients with AR [androgen receptor] alterations. So, 2 of the arms have been reported, cabozantinib and rucaparib. Cabozantinib was negative, but there was some negative selection going on because the DNA damage repair and the AR, we don’t know if they are higher risk. Maybe there were some selection issues. So cabozantinib was not superior to placebo. While rucaparib was trending strongly, there wasn’t a good separation of PFS, which was a primary end point. This was a well-selected population. So I think that we need more data in terms of a definitive phase 3 trial to have a PARP inhibitor for this disease.
Petros Grivas, MD, PhD: Interesting. For now, as you mentioned, there is some signal for PARP inhibition, but it’s still too early to define that signal further. There’s an ongoing trial by Shilpa Gupta, MD, and colleagues called MAIN-CAV, which is switch-maintenance cabozantinib plus avelumab vs avelumab alone, right?
Guru P. Sonpavde, MD: That’s right. That is a VEGF plus PD-L1 combination that is building upon the avelumab switch-maintenance space. You must also recall that in the LEAP 011 trial, the combination of a different VEGF inhibitor, lenvatinib, with pembrolizumab was not superior to pembrolizumab in the first line. It was mostly a platinum-ineligible population that was enrolled in the trial, unfortunately.
Petros Grivas, MD, PhD: It’s interesting how we define those platinum-ineligible patients. In our practice, probably a low proportion cannot get carboplatin, probably 10% to 20% in my practice cannot get carboplatin. But there is definitely a need for more trials in this population.
Transcript edited for clarity.