mRCC: Atezolizumab after progression with prior ICI treatment shows no benefit and increases toxicity

Share :
Published: 5 Jun 2023
Views: 73
Dr Toni Choueiri - Dana-Farber Cancer Institute, Boston, USA

Dr Toni Choueiri speaks to ecancer about the primary progression-free survival analysis from the phase 3, randomised, open-label CONTACT-03 study.

The study investigated the efficacy and safety of atezolizumab administered with cabozantinib as opposed to administering cabozantinib alone after progression with prior immune checkpoint inhibitor (ICI) treatment in metastatic renal cell carcinoma (RCC).

Dr Choueiri says the findings demonstrate that the addition of atezolizumab to cabozantinib did not improve clinical outcomes and that the progression-free survival was around 10-11 months in both arms of the trial. 

Moreover, the combination had higher toxicity compared to the control arm cabozantinib.

CONTACT-03 was a randomised phase III trial that tested the efficacy of, in general, PD-1/PD-L1 rechallenge after progression on prior PD-1/PD-L1 inhibitor. It had a very interesting and very particular design in that it added to a control arm, cabozantinib, one drug atezolizumab. So patients with kidney cancer, with clear cell and non-clear cell RCC, who experience progression on prior drugs like pembrolizumab and nivolumab were randomised to cabozantinib plus atezolizumab versus cabozantinib. 

This is a very important question; it's a question that deals also not just with kidney cancer but deals also with solid tumours in general. Can we rechallenge with a different immune checkpoint inhibitor in a very well-controlled setting where the only thing in addition to the control arm is the PD-1/PD-L1 inhibitor? We see practices, at least around me in the United States, where patients go from one to another PD-1 inhibitor. I've seen it in renal cell cancer, I've seen it in bladder cancer, and if you look at the literature you see it in other malignancies such as melanoma and lung cancer. This is the data that comes from real world practice. 

So what we did here, and the finding showed that there is no advantage in terms of progression free survival, the primary endpoint, response rate, complete responses or overall survival to switching to another immune checkpoint inhibitor. Even more, the combination had higher, at least numerical, toxicity compared to control arm cabozantinib. The PFS was around 10-11 months in in both arms. 

So, I think the biggest thing is that I want to take this out of renal cell cancer and say that it has implications for other solid tumours when you try to change an immune checkpoint inhibitor, obviously after progression and tolerance on the first one. 

This was a group effort led by many folks, including the first author, Dr Monty Pal, who was my co-Chair, as well as several members of the steering committee: Dr Albiges, Dr Suárez, Dr Voss and others. This was an international global study that was presented in the oral GU session at ASCO. 

How can these results impact the future treatment of renal cell carcinoma?

We have a practice in renal cell cancer, and I I say also in other solid tumours, that sometimes we switch to another immune checkpoint inhibitor. I think we have to be careful outside the clinical trial. The results are are really completely no benefit.

Now you may say it's the drug, atezolizumab, that's fine but atezolizumab is a drug that has single agent activity of 25% in untreated renal cell cancer, so it's an active agent. Now, having said so, we have another trial, very similar design with a different TKI, tivozanib, and a different class of immune checkpoint inhibitor. So we move from PD-L1 inhibitor with atezolizumab to a PD-1 inhibitor with nivolumab. So that's called the TiNivo-2 study: tivozanib versus tivozanib plus nivolumab in patients whose disease has progressed on prior PD-1 and PD-L1 inhibitor. 

This study is currently, at the time of the conduct of this interview, accruing, accruing well and hopefully will close soon and then we will have an answer.  If this study comes again with no benefit, I think this is another fact that will question the validity of rechallenging with PD-1 and PD-L1 inhibitors after progression. Of course, this is after progression, meaning patients should have tolerated their first drug, should have received enough PD-1/PD-L1 inhibitor, the immediate therapy was the PD-1/PD-L1 inhibitor. It doesn't answer the question of whether a patient, who had couple of doses then got multiple other treatments and then after a couple of years restarted - could they restart checkpoint inhibitor? So you have to stick to the eligibility of each study.