CheckMate-227 Regimen Safety Profile

Neal E. Ready, MD, PhD: There was a good overall response rate, the immunotherapy. It was clearly better than we would have thought from single agent PD-1 checkpoint treatment, it was over 30%, which was very respectable. The duration of response was excellent. The duration of response was around 18 months which was very strong. The progression-free survival looked about the same as chemotherapy, which is not surprising for an immunotherapy alone combination. The response rate for the nivo/ipi was good, better than for chemotherapy. The duratioThe safety of the nivo/ipi combination was that it was safe and feasible. So certainly when you give combination immunotherapy you're going to have more side effects then if you give a single PD-1 checkpoint treatment. Originally when nivolumab and ipilimumab was developed, it was developed in melanoma patients and higher doses of ipilimumab were used, a more frequent dosing of ipilimumab was used. And that combination of nivolumab and ipilimumab was not safe or feasible in lung cancer patients. We did a large phase 1 trial called CheckMate-12 and we carefully evaluated the combination of these immunotherapies and determined that if we gave the ipilimumab, 1 mg/kg, every six weeks, that that was safe and feasible in lung cancer patients.

The safety of the nivo/ipi combination was that it was safe and feasible. When you give combination immunotherapy you're going to have more adverse effects then if you give a single PD-1 checkpoint treatment. Originally when nivolumab and ipilimumab was developed, it was developed in melanoma patients and higher doses of ipilimumab were used, a more frequent dosing of ipilimumab was used. And that combination of nivolumab and ipilimumab was not safe or feasible in lung cancer patients. We did a large phase 1 trial called CheckMate-12 and we carefully evaluated the combination of these immunotherapies and determined that if we gave the ipilimumab, 1 mg/kg, every six weeks, that that was safe and feasible in lung cancer patients. And this large randomized phase III trial confirmed that and so did a large phase II trial, CheckMate-568. You'll see about 30% to 40% grade 3 or grade 4 toxicity with a nivolumab and ipilimumab combination, which is more than you'd expect for instance than nivolumab alone. But less than 20% of patients discontinued any component of their treatment due to toxicity, which was a solid result. And there were no significant more deaths, in fact, there were very few deaths and comparable to the chemotherapy arm. While the combination immunotherapy is clearly more toxic than a single immunotherapy, it was safe and feasible and generally comparable to what one might expect for chemotherapy treatment.

Stephen Liu, MD: CheckMate-227 looking at dual checkpoint blockade with nivolumab and ipilimumab is chemotherapy-free, but it’s not toxicity-free. If you look at treatment-related adverse events, 77% incidence, although that’s lower than chemotherapy, which was just over 80%. Grade III to IV adverse events, similar, 33% versus 36%. If you look at treatment-related tox leading to discontinuation of therapy, that occurred about 18% of the time versus 9% with chemotherapy. The toxicity that we see with dual checkpoint blockade tends to be early. In my own practice I’ve been pleasantly surprised. I think a lot of it has to do with ipilimumab dosing. Using CTLA-4 in different cancers is challenging, and the dosing regimens vary from disease to disease. This low-dose approach using ipilimumab at a dose of one milligram per kilogram every six weeks has been much better tolerated than my previous efforts.

Neal E. Ready, MD, PhD: How the CheckMate 227 nivolumab-ipilimumab regimen fits into a first-line treatment of lung cancer is complex, which is good. We have a lot of good choices in first-line treatment. For tumors that have very high PD-L1s, so 50% or higher, and particularly for ones that are 70%, 80%, 90%, 100%, pembrolizumab alone is an approved therapy, and it can be very effective in that population with minimal toxicity. For patients with non–small cell lung cancer, a chemotherapy doublets with an immunotherapy such as pembrolizumab or atezolizumab were approved, and those are good options. The CheckMate 227 regimen of nivolumab and low-dose ipilimumab will give us an effective chemotherapy-free combination that we can offer to our patients who are not good candidates for chemotherapy, or for patients who for 1 reason or another want to avoid chemotherapy. A lot of people from personal experience or experiences with their families will want to avoid chemotherapy if they can. There may be patients who have particular aversions to nausea or hair loss or some other toxicity that is common with chemotherapy, so they would really prefer to have a chemotherapy-free option. The CheckMate 227 combination provides that, and you feel confident about that for most non–small cell lung cancer patients.

Transcript Edited for Clarity