Personalizing Immunotherapy in NSCLC Using PD-L1 and Tumor Mutation Burden as Biomarkers
Tumor expression of PD-L1 has consistently predicted response and survival outcomes in non–small-cell lung cancer (NSCLC), whereas the role of PD-L1 in immune cells is unclear, said Edward B. Garon, MD, Director, Thoracic Oncology Program, David Geffen School of Medicine, University of California, Los Angeles, at the 2019 ASCO-SITC Clinical Immuno-Oncology Symposium.
Tumor mutation burden (TMB) also consistently predicts objective response rate, as well as progression-free survival (PFS) in NSCLC.
In the phase 1 KEYNOTE-001 study, patients with PD-L1 expression on at least 50% of the tumor cells were 3 to 4 times more likely to have a response to pembrolizumab (Keytruda) than those with no PD-L1 expression. This finding was true in the total study population, for those who had received previous treatment, and in the treatment-naïve population.
In addition, the PFS and overall survival (OS) were better among patients who had PD-L1 of at least 50% compared with the other patients.
This correlation was validated as part of the KEYNOTE-024 study, which enrolled 305 patients with NSCLC, all of whom had high PD-L1 expression. Patients were randomized to pembrolizumab or to a platinum-based dual-chemotherapy treatment. The PFS favored pembrolizumab, and although crossover from chemotherapy to pembrolizumab was allowed at disease progression, the OS still favored the pembrolizumab arm.
“There has been a great deal of debate as to the generalizability of PD-L1 expression,” Dr Garon said.
In the CheckMate-017 study, which compared nivolumab (Opdivo) with docetaxel (Taxotere) in patients with NSCLC, patients benefited from nivolumab versus docetaxel, regardless of PD-L1 expression, although numerically outcomes “did look better in the PD-L1–expressing patients,” he said.
Among patients with nonsquamous NSCLC in the CheckMate-057 study, however, a clear difference in outcomes was seen by PD-L1 expression. In patients with PD-L1 expression >10%, nivolumab demonstrated superior OS to docetaxel. “Nearly the entirety of the OS benefit was in patients who had staining for PD-L1 in ≥10% of cells,” Dr Garon said.
In the randomized, open-label pivotal OAK trial, which compared atezolizumab (Tecentriq) with docetaxel in patients with NSCLC, the OS superiority of atezolizumab was similar in the intent-to-treat population and in the subset of patients with PD-L1 expression.
“One thing to note about the atezolizumab biomarker is it’s different from the other PD-L1 biomarkers that have been assessed,” Dr Garon said. “They looked for PD-L1 not just on the tumor cells, but also on the immune cells.”
PD-L1 expression may be used to select responders to atezolizumab only when PD-L1 expression is in the top 15%, he added.
In the OAK study, a strong positive result was observed with atezolizumab in patients with PD-L1 expression of ≥50%. It showed no advantage over chemotherapy in patients with lower PD-L1. Including these patients with those with high PD-L1 expression, therefore, weakens the predictive capability of the PD-L1 biomarker, Dr Garon argued.
One concern with the use of immune-infiltrating PD-L1 cells is that “if you show multiple pathologists the same slide, they generally do not agree,” Dr Garon said. “That obviously is a problem for a biomarker.”
The 50% cutoff point for PD-L1 expression in NSCLC is reasonable, he suggested. In an exploratory analysis of the KEYNOTE-024 study, pembrolizumab improved OS versus chemotherapy in patients with untreated advanced or metastatic NSCLC and a PD-L1 expression of ≥50%.
The difference in OS between groups was not significant in those with a PD-L1 expression of ≤49%. “Certainly in my practice, this is not a group where I would look for single-agent PD-1 inhibition, and instead would look at the immunochemotherapy combinations,” Dr Garon added.
Tumor Mutation Burden
In the KEYNOTE-001 study, higher TMB was associated with durable clinical benefit in patients with NSCLC who received treatment with pembrolizumab. In the CheckMate-026 study, which compared front-line nivolumab versus chemotherapy, a retrospective analysis showed that patients with high TMB had superior PFS in the nivolumab arm; by contrast, in those with low or medium TMB, chemotherapy outperformed nivolumab.
Despite the improvement in PFS by TMB, TMB had no effect on the OS. This finding was replicated in a study of nivolumab plus low-dose ipilimumab (Yervoy) compared with chemotherapy, in which the hazard ratio for OS in favor of the combination therapy was 0.77 in patients with TMB ≥10 mutations compared with 0.78 in patients with TMB <10 mutations. TMB as a biomarker “won’t be coming to the clinic any time soon,” Dr Garon predicted.
Nearly 50% of the patients who received treatment in clinical trials did not have enough tissue available for assessment of TMB, Dr Garon noted. Furthermore, TMB values obtained by different laboratories are not necessarily reproducible. Blood TMB addresses some of the issues with a lack of tissue availability, but it does introduce additional variability based on shedding of DNA from tumors, he concluded.
Data from the TRACERx lung study suggest that circulating tumor DNA (ctDNA) may be a biomarker for the detection of postsurgical minimal residual disease (MRD) in patients with non–small-cell lung cancer (NSCLC), suggesting which patients are at increased risk for disease relapse and will require more aggressive adjuvant therapy.
According to data from a preliminary phase 1b clinical trial, a novel approach using the investigational toll-like receptor 9 (TLR-9) agonist CMP-001 in combination with pembrolizumab may have the potential to reverse resistance to anti–PD-1 therapy.