Discussant for the CheckMate 227 and CheckMate 9LA trials, Scott N. Gettinger, MD, of Yale Cancer Center in New Haven, Connecticut, said: “There is tremendous interest in lung cancer to combine nivolumab plus ipilimumab, driven by the melanoma experience. However, combinations of immunotherapy come with more toxicity.”

Scott N. Gettinger, MD

Regarding the recent U.S. Food and Drug Administration (FDA) approval of nivolumab plus ipilimumab for patients with PD-L1 ≥ 1% expression, Dr. Gettinger said: “This combination is a new first-line option for PD-L1–expressing NSCLC [non–small cell lung cancer].”

Questions and Considerations

The question is whether this is an option for PD-L1–negative NSCLC. “The FDA says no, because the PD-L1–negative population was not included in the primary analysis, but the combination is recommended in the NCCN^® [National Comprehensive Cancer Network^®] Guidelines for both PD-L1–positive and PD-L1–negative metastatic nonsquamous NSCLC, and it will likely be covered by insurance in the United States.”

In CheckMate-9LA, treatment was not determined by PD-L1 status (as it was in CheckMate-227). The primary endpoint was met, with an absolute improvement in survival of 4.7 months for nivolumab/ipilimumab plus two cycles of chemotherapy.

“The main difference between the two CheckMate trials is that the minimum follow-up of 12.7 months for 9LA is about one-third of the 3-year follow-up of CheckMate-227. We need longer follow-up of CheckMate-9LA,” Dr. Gettinger pointed out.

“Nivolumab/ipilimumab plus limited chemotherapy is superior to chemotherapy alone regardless of the level of PD-L1 expression. However, this is not a new option yet. The FDA is expected to  make a decision on this by August 2020, when results of the POSEIDON trial are reported,” he said.

The big question is how to choose a first-line option for patients with no mutations. “We need head-to-head trials, but they are unlikely to be conducted. Toxicity and cost will need to be considered. Most important is that we need a better understanding of the biology in order to select patients for a specific treatment. CheckMate 592 will enroll patients with treatment-naive stage IV or recurrent NSCLC and treat them with nivolumab plus ipilimumab, obtaining specimens from blood, tissue, and stool. This may help identify biomarkers,” Dr. Gettinger said.

Making Treatment Decisions

“I was asked to share my approach to making treatment decisions tomorrow,” Dr. Gettinger continued. “Mine may be different from other approaches.” Once the traditional factors are considered, he suggested the following steps:

For PD-L1–negative NSCLC, use chemotherapy/immunotherapy with either pembrolizumab or atezolizumab (only approved for nonsquamous NSCLC); and if approved, nivolumab/ipilimumab plus chemotherapy is another option. If patients do not want to be treated with chemotherapy and disease is not overly symptomatic or aggressive, they could consider nivolumab plus ipilimumab.

For NSCLC with PD-L1 expression of 1% to 49%, he would use chemotherapy/immunotherapy, and if not overly symptomatic or aggressive, he would consider immunotherapy alone. “At our institution, in the COVID-19 era, consider pembrolizumab alone because of concerns about chemotherapy,” he said.

For high tumor PD-L1 (> 50%) NSCLC, he tends to recommend pembrolizumab alone, although atezolizumab is another option.

For smokers, regardless of PD-L1 expression, use chemotherapy plus immunotherapy; if disease is not overly symptomatic or aggressive, he would consider nivolumab plus ipilimumab.

“There are at least 11 ongoing phase III trials evaluating combinations with immunotherapy, and we should have more evidence from them,” Dr. Gettinger said. 

DISCLOSURE: Dr. Gettinger has served in a consulting or advisory role for Bristol-Myers Squibb and Nektar and has received research funding from Ariad/Takeda, Bristol-Myers Squibb, Genentech, Incyte, and Iovance Biotherapeutics.