CHICAGO—“Lung cancer is the greatest cause of cancer death worldwide and for most patients with newly diagnosed advanced non-small cell lung cancer (NSCLC), chemotherapy has long been the standard,” said Matthew Hellmann, MD, assistant attending at Memorial Sloan Kettering Cancer Center. “While PD-1 immunotherapies have recently emerged as a critical new treatment option for this patient population, only a minority of all patients with NSCLC respond.
“This context has yielded two critical opportunities for improvement: to develop effective combinations of therapy that can broaden the population of patients who respond to immunotherapy, and to identify useful biomarkers to effectively predict response,” Hellmann explained. To that end, CheckMate-227, an open-label, multipart, phase III clinical trial was initiated.
“In this study,” Hellmann noted, “we examined progression-free survival with the anti-programmed death 1 (PD-1) antibody nivolumab in combination with ipilimumab, an anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) antibody versus chemotherapy among patients with high tumor mutational burden (TMB).
“Based on rapidly emerging data suggesting the importance of TMB as a predictive biomarker for benefit with immunotherapy, CheckMate-227 was amended to include—in addition to the initial study design examining nivolumab plus ipilimumab in PD-L1 selected patients—a co-primary endpoint of nivolumab plus ipilimumab versus chemotherapy in patients with high TMB, pre-defined as 10 or more mutations per megabase (Mb),” Hellmann said
“The results show that in patients with TMB-high NSCLC nivolumab plus ipilimumab provides improved benefit compared to chemotherapy, increases benefit compared to anti-PD-1 monotherapy, yields durable responses, spares the use of chemotherapy in the first-line setting, and could preserve an effective option in the second line of therapy, if needed,” he added.
Recently, these results were presented by Hellmann at the 2018 AACR Annual Meeting. Simultaneous to that presentation was the publication of the results in the New England Journal of Medicine (2018; doi:10.1056/NEJMoa1801946).
Patients were deemed eligible for participation in this study if they met the following criteria: adult (i.e., 18 years or older); had histologically confirmed stage IV or recurrent squamous or non-squamous NSCLC; an ECOG performance status score of 0 or 1; had received no prior systemic anticancer therapy as their primary therapy for disease in the advanced or metastatic setting; had no therapeutically targetable known EGFR mutations or ALK translocations; and had no autoimmune disease.
To be eligible for participation in this study, it was necessary for patients with central nervous system (CNS) metastases to be adequately treated and had neurologic criteria returned to baseline (with the exception of residual signs or symptoms attributable to CNS therapy) for at least 2 weeks prior to randomization.
CheckMate-227 is a multi-part phase III trial which sought to evaluate different nivolumab-based immunotherapy regimens versus chemotherapy in distinct patient sub-populations. Patients were enrolled with a tumor PD-L1 expression level of ≥1 percent at the same time as those patients having levels <1 percent at the same centers.
Eligible participants having a PD-L1 expression levels of ≥1 percent were stratified according to tumor histologic type (squamous vs. nonsquamous) and randomized in a 1:1:1 ratio to receive: nivolumab (3 mg/kg, Q2W) plus ipilimumab (1 mg/kg Q6W); platinum doublet chemotherapy (based on tumor histologic type) Q3W for up to four cycles; nivolumab (240 mg Q2W). Those patients having PD-L1 expression levels <1 percent were also stratified according to tumor histologic type and randomized in a 1:1:1 ratio to receive: nivolumab (3 mg/kg, Q2W) plus ipilimumab (1 mg/kg Q6W); platinum doublet chemotherapy (based on tumor histologic type) Q3W for up to four cycles; nivolumab (360 mg) plus platinum doublet chemotherapy (based on tumor histologic type) Q3W for up to four cycles.
Nonsquamous NSCLC patients who had stable disease or a response (i.e., partial or complete response) after four cycles of chemotherapy or chemotherapy plus nivolumab could continue with maintenance pemetrexed or pemetrexed plus nivolumab. All therapies were continued until disease progression (PD), unacceptable adverse effects, or completion as defined by the protocol (≤2 years for immunotherapy). No crossover between treatment groups was permitted within this trial.
There were two coprimary endpoints for part 1 of the CheckMate-227 trial. The first was progression-free survival (PFS), which was assessed by blinded independent centralized review to compare nivolumab plus ipilimumab versus chemotherapy in patient populations based on their TMB values. From data obtained in the prior CheckMate-568 study, a prespecified cutoff for TMB of ≥10 mutations/Mb was selected for preplanned analysis of the coprimary endpoint. The other coprimary endpoint is overall survival (OS) for comparing nivolumab plus ipilimumab versus chemotherapy in patients based on their PD-L1 expression levels.
Between August 2015 and November 2016, 2,877 patients were enrolled in part 1 of CheckMate-227, and of these, 1,739 were randomized. For the 1,138 patients who did not undergo randomization, 909 no longer met the criteria for inclusion in this study. Common reasons for exclusion included ALK or EGFR mutations/translocations, decline in ECOG PS scores, untreated CNS metastases, and missing data for PD-L1 expression.
Across all treatment groups, there were 1,004 patients whose TMB could be evaluated, and of these, 444 (44.2%) had ≥10 mutations/Mb. Among these participants were 139 and 160 patients who were randomized to the nivolumab plus ipilimumab and chemotherapy groups, respectively. Characteristics at baseline were generally well-balanced between the two treatment groups, including factors such as PD-L1 expression levels. “There was no correlation between TMB and PD-L1 expression levels—importantly, they are independent variables,” Hellmann noted.
Among all randomly assigned patients (i.e., irrespective of TMB and PD-L1 expression levels), the 1-year PFS rate was higher for patients in the nivolumab plus ipilimumab group than those in the chemotherapy group (30.9% vs. 17.0%), giving a hazard ratio (HR) for PD or death of 0.83 (95% CI: 0.72-0.96).
Coprimary endpoint analysis of patients having high TMBs showed significantly longer PFS for those in the nivolumab plus ipilimumab group than participants in the chemotherapy group. The 1-year PFS rate was 42.6 percent versus 13.2 percent for the nivolumab plus ipilimumab and chemotherapy groups, respectively; the median PFS values for these two groups were 7.2 months (95% CI: 5.5-13.2 months) and 5.5 months (95% CI: 4.4-5.8 months), respectively, affording an HR for PD or death of 0.58 (97.5% CI: 0.41-0.81; P<0.001). Prespecified multivariate analysis of PFS among patients having high TMBs showed that the treatment effect of nivolumab plus ipilimumab versus chemotherapy, when adjusted for baseline PD-L1 expression levels (≥1% vs. <1%), sex, tumor histologic type (squamous vs. nonsquamous), and ECOG performance-status score (0 vs. ≥1), was consistent with that in the primary PFS analysis (HR for PD or death, 0.57 (97.5% CI: 0.40-0.80; P<0.001 by multivariate Cox model)).
The objective response rate (ORR) was 45.3 percent for the nivolumab plus ipilimumab group, and of those patients 68 percent had an ongoing response after 1 year. For the chemotherapy group, the ORR was 26.9 percent, with 25 percent of that group having an ongoing response after 1 year.
For patients with low TMB (i.e., <10 mutations/Mb), the HR for PD or death was 1.07 (95% CI: 0.84-1.35) for the nivolumab plus ipilimumab versus chemotherapy. Hellmann commented, “For patients with low TMB, there was no benefit to nivolumab plus ipilimumab. This result highlights the value of the TMB biomarker and the effectiveness of the pre-specified cutpoint in identifying those patients most likely to benefit.”
Regarding the clinician's finding in this study, Hellmann observed, “The results of this trial show that, in patients with advanced NSCLC and a TMB of ≥10 mutations/Mb, first-line treatment with nivolumab plus ipilimumab was associated with significantly longer PFS than chemotherapy.
“The benefit of combination immunotherapy was durable, with 43 percent of patients being progression-free at 1 year (vs. 13% with chemotherapy) and 68 percent of those with a response having ongoing responses at 1 year (vs. 25% with chemotherapy).”
In patients with high TMB, an equivalent benefit for nivolumab plus ipilimumab was observed for those with either PD-L1 expression levels of ≥1 percent or <1 percent, as well as in patients with a squamous or nonsquamous tumor histologies; the benefit was also consistent across the majority of other subgroups.
“Although longer PFS was seen with nivolumab plus ipilimumab than with chemotherapy among all randomly assigned patients, a TMB of ≥10 mutations/Mb was an effective biomarker,” Hellmann said. “The benefit with nivolumab plus ipilimumab was particularly enhanced in patients with a high TMB. PFS at 1 year was nearly tripled, 43 percent versus 13 percent, as was the duration of response at 1 year, 68 percent and 25 percent.”
“The first endpoint data presented here examined PFS among patients with high TMB,” he continued. “Importantly, TMB appears to be completely independent of PD-L1 expression levels and characterizes about 45 percent of patients with NSCLC.
“OS data are still maturing and will add further insight into the clinical benefit of nivolumab plus ipilimumab as a first-line option for NSCLC patients with high TMB,” he observed.
“Nivolumab plus ipilimumab was well-tolerated and the safety profile was similar to the previous experience with this regimen; the rate of treatment-related grade 3-4 toxicities was 31 percent versus 36 percent with chemotherapy.
“These potentially practice-changing data establish the combination of nivolumab plus ipilimumab as a first-line treatment option for patients with high-TMB NSCLC,” Hellmann said. “This work also identifies TMB as an important and reliable biomarker that should be tested in patients with newly diagnosed NSCLC.”
Richard Simoneaux is a contributing writer.