Nivolumab plus Ipilumumab in NSCLC: A New Use for Tumor Mutational Burden?

This study asks if we can add tumor mutational burden (TMB) as actionable information, and should we perform this test on all NSCLC specimens. The theory is that tumors with high TMB will express more foreign antigens, and thus be more responsive to immune checkpoint inhibition. Reviewing the literature, there has been varying correlation between TMB and response to immunotherapy [3]. Despite its potential use as a biomarker, no prior study has shown that using any treatment in a high TMB population conveys any benefit and thus it is not considered standard of care to test for TMB.

This article’s conclusion has several major implications. First, does dual immunotherapy have a role in NSCLC? The data in the trial shows that in high TMB patients there is a clear PFS benefit to nivolumab plus ipilimumab over chemotherapy. In addition, about 40% of patients had a durable response at 2 years follow-up. Strengths of this study are the large size, although smaller when selected for only high TMB patients. Another strength is the long follow-up with a minimum of 11.2 months, with a significant number followed for about 2 years. A weakness of this trial is that patients were randomized before their TMB status was known. In addition, only 57.7% of the randomized patients were able to be analyzed for TMB. The third arm of this study (nivolumab monotherapy), while providing the information that it is less effective in this population, does cloud the information. Finally, while a benefit in PFS was found in the TMB cohort, this does not always correlate with an OS benefit in mature data.

Second, if it does have a role, should TMB be a standard test on all NSCLC specimens? While it was borderline, there was no benefit to squamous histology. In the supplemental index it was reported that nivolumab monotherapy did not show a benefit, thus the need to offer ipilimumab depends on TMB status. Pembrolizumab is already approved in patients with PD-L1 expression greater than 50% [2]. However, in patients with PD-L1 less than 50% and no ALK or EGFR mutation, chemotherapy would be frontline treatment; with TMB testing these patients could be spared this toxic treatment. In addition, a parallel published study shows benefit to adding pembrolizumab to standard chemotherapy [4].

Another consideration is the requirements of tissue for testing TMB. This study used the Foundation One assay. This test required optimally 25 square millimeters of tissue and preferred the whole block of tissue or 10 unstained slides [5]. For patients who are diagnosed with full surgical resection this is not an issue and should not be a barrier for this therapy. However, metastatic disease patients are often diagnosed on core biopsy of a metastatic site, thus getting an accurate TMB profile (in addition to testing other actionable mutations) could be a challenge. Identifying patients who would be a candidate for this therapy prior to biopsy will be important given the tissue requirements.

Another advantage to immunotherapy vs standard chemotherapy has been favorable toxicity rates. PD-L1 inhibitor monotherapy has generally been superior to standard chemotherapy and has been a better option for frail patients. However, the addition of the CTLA-4 inhibitor ipilimumab to PD-L1 blockade has increased the toxicity profile. In this trial, the grade 3 or greater toxicity rate was similar between dual immunotherapy and chemotherapy, although with different major symptoms. In addition, patients with prior autoimmune disease or active brain metastasis were excluded from the study and thus should not be offered dual immunotherapy. A clinician will need to consider if their patient is a candidate for dual immunotherapy before considering the application of this trial.