2019 Lung Cancer Fall Preview - Episode 4

Updated Data in Stage IV NSCLC: CheckMate-227


Suresh Ramalingam, MD: When patients don’t have driver mutations for non—small cell lung cancer, the frontline approach is immunotherapy [I/O] given by itself or in combination with chemotherapy. Multiple studies have shown that chemotherapy given with pembrolizumab or chemotherapy given with bevacizumab and atezolizumab are effective strategies in the frontline setting. The other strategy that’s been under evaluation is the combination of ipilimumab and nivolumab, which is a nonchemotherapy combination, both agents targeting the immune pathway. We know that the combination of ipilimumab and nivolumab is successful in improving patient outcomes for metastatic melanoma. In non–small cell lung cancer, we have seen data from phase II studies earlier that showed promising outcomes in terms of response rate and progression-free survival [PFS].

The CheckMate-227 trial was specifically designed to ask a few questions. It’s a large trial with close to 2000 patients enrolled. One question was to compare the outcomes of ipilimumab plus nivolumab to either nivolumab alone or chemotherapy in patients with high PD-L1 [programmed death-ligand 1] expression. That group enrolled about 1150 patients. The next group was for patients with low PD-L1 expression where the randomization was to nivolumab plus ipilimumab versus chemotherapy alone versus chemotherapy plus nivolumab. So one of the arms in the PD-L1—high and PD-L1–low was slightly different.

What we are looking forward to is seeing the results of the outcome with ipilimumab and nivolumab based on PD-L1 expression. We have seen data based on tumor mutation burden [TMB] last year at the AACR [American Association for Cancer Research] meeting and subsequently in a New England Journal of Medicine publication where if patients had a higher tumor mutation burden, defined as 10 mutations per mega base, the combination of ipilimumab plus nivolumab was superior to chemotherapy alone in terms of PFS. But what we later found out is that those results were also seen in patients with low TMB, which raised questions about whether TMB itself is a good predictor marker or is it just a prognostic marker.

The CheckMate-227 trial that we’re looking forward to hearing about in the next few weeks is going to report on the PD-L1 expression as a predictor of outcome with ipilimumab plus nivolumab. The press release from the sponsor noted that the study met its primary endpoint, showing superiority for ipilimumab plus nivolumab in the high PD-L1 group compared to chemotherapy alone. So at the meeting, we obviously would want to know what the PFS improvement with ipilimumab plus nivolumab combination was, what the impact on overall survival was, and also more information on the safety profile. This being a very large trial, we will have enough information to do even subset analysis to understand other questions on top of the topline biomarker question. My hope is that after the results are reported, we will have more clarity on which group of patients can get I/O alone, which subset of patients need chemotherapy plus I/O, and if there is a subset of patients who can get an I/O plus I/O combination for frontline therapy of non—small cell lung cancer.

When the ipilimumab plus nivolumab regimen was initially developed, the main question was, will it be safe enough for patients with lung cancer? As a response to that question, the investigators looked at various dosing schedules and came up with a dosing of nivolumab given at 3 mg/kg every 3 weeks and ipilimumab given at 1 mg/kg every 6 weeks. With that regimen, the tolerability seems to be very good. This is very different from the dosing schedule that’s used in the melanoma setting where more ipilimumab is given compared to the relative nivolumab dose. Now that we know that this regimen is relatively safe, looking at the efficacy outcomes based on PD-L1 expression would, I believe, shed new light on the optimal role for this agent in the setting of non—small cell lung cancer. Eventually having more options will allow us to individualize therapy to patients based on biomarker status, patient preference, toxicity profile, and ultimately the cost of care as well.

Transcript Edited for Clarity