Immunotherapy Monotherapy in Later-Line Setting

Richard S. Finn, MD: Pierre you brought up an important idea, and Tony gave us some thoughts of using ramucirumab after prior bevacizumab. Katie, is there a role for IO [immune-oncology] after IO? We learned about ipilimumab/nivolumab in the second-line setting after prior sorafenib, and we now have lenvatinib/pembrolizumab. You presented data on durvalumab/tremelimumab, though it’s not approved.

Katie Kelley, MD: It’s a tricky question. How do we handle IO monotherapy in the later lines of therapy now, or the nivolumab/ipilimumab? After atezolizumab/bevacizumab, we don’t yet have much level 1 evidence to work with. I agree with the comments earlier that cabozantinib had the most permissive phase 3 design in the CELESTIAL trial and has rationale there. In making the decision, there are a couple of considerations to factor in.

For atezolizumab/bevacizumab, one that we haven’t yet talked about is this report of a substantial 27% of patients having anti-drug antibodies [ADA] to atezolizumab, which don’t seem to occur with such frequency when compared to some of the other agents. They all have some potential for this. We don’t yet have a clinical test, but there is some potential concern that patients may have a lack of efficacy owing to ADAs. This is theoretical, and we’re hand-waving because we can’t test for them in the clinic yet, but it does raise the consideration for a patient who tolerated atezolizumab/bevacizumab but progressed quickly and then received a second-line TKI [tyrosine kinase inhibitor] agent, whether it was lenvatinib, cabozantinib, or whichever was chosen, and they were still fit for a third-line therapy.

It’s not unreasonable to consider nivolumab/ipilimumab as a combination in a fit patient who doesn’t have another treatment option and had progressed on atezolizumab/bevacizumab. There is that consideration under the premise that perhaps there was an interfering antibody that prohibited response. In the patients who haven’t received first-line atezolizumab/bevacizumab and received a first-line TKI either because they started treatment pre-atezolizumab/bevacizumab or because they had a contraindication at the time but have now removed that contraindication, there was also the question.

There is also a good discussion to be had about whether to go down the road of a second-line TKI, third-line agent like ramucirumab vs switching to an IO agent. This is where there’s some anecdote or clinical instinct that may or may not be valid in terms of how well the patient did on their first-line TKI. I have patients who progressed quickly on a TKI, so I might be inclined to try nivolumab or pembrolizumab in the second-line setting or nivolumab/ipilimumab if they’re fit rather than doing a second-line TKI. This is based on the gestalt of response to the first-line regimen, though we don’t have great data for this.

Another consideration, to bring up something that was presented at ESMO [the European Society for Medical Oncology Virtual Congress], is that we’ve seen recent trends that PD-L1 tumor expression seemed to have a trend toward an improved response rate with nivolumab and pembrolizumab and atezolizumab/bevacizumab. It’s preliminary, we don’t have that data yet, but at for least nivolumab and pembrolizumab, there is a meta-analysis from ESMO this year that suggests that the rate of response was almost 2-fold for patients with PD-L1 positive tumor expression, in a meta-analysis of about 900 patients. I’m not advocating to go out and start checking PD-L1 in all of our patients’ tumors, but it does raise the question of whether we can study this more prospectively.

Transcript edited for clarity.