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Results of the phase II PRISM trial for advanced renal cell carcinoma (RCC) suggested that a modified dosing schedule for ipilimumab (once every 12 weeks instead of 3 weeks) in combination with nivolumab was still effective but reduced toxicity.

"The opportunity to optimize the dose and schedule of drugs, including immune checkpoint inhibitors, in cancer care to reduce cost, widen access, and improve safety is increasingly being recognized, as exemplified by initiatives such as the U.S. Food and Drug Administration's Project Optimus," Naveen Vasudev, MD, PhD, of the University of Leeds in the U.K., and colleagues wrote in the .

In the 192 patients randomized to the standard or modified dosing and followed for approximately 2 years, the incidence of grade 3-5 treatment-related adverse events (trAEs) was not surprisingly significantly lower in patients on the modified dose (32.8% vs 53.1%, OR 0.43, P=0.0075), the study found.

The incidence of trAEs was the study's primary endpoint, but it was not powered to compare the treatment arms for efficacy. However, the researchers observed no clear differences in response rate, progression-free survival, or overall survival, they said.

"Our data are consistent with studies in melanoma and NSCLC, suggesting that low dose and/or increased interval dosing of ipilimumab, in combination with anti–PD-1 blockade, can remain efficacious while reducing toxicity experienced by patients," the researchers concluded.

Vasudev elaborated on the details of the study and offered additional perspective in the following interview.

Focusing on adverse events rather than efficacy as a primary end point is unusual, but not unprecedented. Why did you choose trAEs as the primary endpoint?

Vasudev: Yes, choosing safety, rather than efficacy, as a primary endpoint in the setting of a Phase II trial is somewhat novel and challenges the established paradigm.

This was a pragmatic design, allowing direct comparison of arms for safety (the primary objective of the study), whilst the efficacy data collected in the standard arm allows readers to ascertain whether the trial population performs similarly to other studies, and to allow secondary informal comparison of efficacy outcomes to ascertain whether there are any major concerns with efficacy signals in the experimental group.

We suspect that such trial designs are likely to become more commonplace, given the growing emphasis around dose and schedule optimization of cancer drugs in oncology.

How did your efficacy data compare with previous studies such as CheckMate 214?

Vasudev: Efficacy data were broadly comparable to , when considering PFS [progression-free survival], OS [overall survival], and ORR [overall response rate]. The exception to this was the CR [complete response] rate, at just 2% versus 10.7% in CheckMate 214. This is likely to have been influenced by the lower nephrectomy rate in PRISM (63%) compared with CheckMate 214 (82%), reflecting a move away from upfront cytoreductive nephrectomy.

Interestingly, a similar CR rate (3%) was also recently reported for the combination in the control arm of the COSMIC-313 trial, which had a comparable nephrectomy rate of 65%.

Large noninferiority trials would be needed to formally compare efficacy of the standard versus modified dose. However, you concluded that such trials did not appear justified on the basis of your results. Why is that?

Vasudev: The findings of this randomized Phase II study, involving almost 200 patients, are compelling in their own right. The results are also consistent with other studies that together reinforce the message that current dose and scheduling of immune checkpoint inhibitors in cancer medicine is very likely to be suboptimal and, specifically, that the timing of CTLA-4 therapy is not crucial to achieve efficacy.

We believe PRISM supports employment of the modified schedule in the clinic, at least in select patients with metastatic RCC, where toxicity may be a particular concern.

There are many other questions that remain unanswered in this field -- for example, can we stop immunotherapy? can we select responders? -- and we must therefore prioritize our research efforts going forward. A Phase III trial testing the same hypothesis seems difficult to justify on this basis.

What did you find in terms of health-related quality-of-life?

Vasudev: This was somewhat surprising, in that we did not detect any significant differences in HRQoL [health-related quality of life] between participants in the two arms of the study. This is despite the significant reduction in grade 3-5 toxicity associated with the modified schedule. We wonder if this reflects shortcomings in current QoL instruments. Not all questions are necessarily relevant in capturing immune-related toxicity. We plan to interrogate the PRISM QoL data further, to understand if a more tailored set of questions may perform better

Is there anything else you would like to make sure oncologists understand about this study?

Vasudev: We have a robust linked translational biobank including longitudinal blood samples and baseline tissue. Biomarker analyses are currently underway – so watch this space!

Read the study here and expert commentary about it here.