Targeted therapy advancements and the identification of emerging biomarkers of response to treatment have led to an improved ability to predict and enhance responses to immunotherapeutic agents in non–small cell lung cancer (NSCLC). Available agents that have contributed to this transformation in recent years include nivolumab (Opdivo) and pembrolizumab (Keytruda), albeit with mixed results.
Additional emerging biomarkers of treatment response and targetable tumor receptors are under investigation, and recent study results presented at 2019 World Conference on Lung Cancer held in Barcelona, Spain, spotlighted the most promising novel agents and strategies for therapy selection that are under development.
The Studies at Hand
In the first randomized phase III trials to report a 5-year outcomes for a PD-1 inhibitor in the setting of previously treated advanced or metastatic NSCLC, CheckMate 017 and CheckMate 057, data demonstrated a 5-year pooled overall survival (OS) rate of 13.4% with nivolumab versus 2.6% with docetaxel and a 5-year pooled progression-free survival (PFS) rate of 8.0% and 0%, respectively. Following treatment with nivolumab, those patients who did not exhibit disease progression at 2 and 3 years exhibited a 60% and 78% chance, respectively, of remaining progression free at 5 years. Furthermore, 10% were no longer receiving nivolumab at 5 years, had not progressed, and had not received subsequent therapy.
Another landmark phase III trial, KEYNOTE-024, included patients with metastatic NSCLC and a PD-L1 tumor proportion score (TPS) of ≥50% who received first-line treatment with pembrolizumab or platinum-based chemotherapy. After at least 3 years of follow-up, patients treated with pembrolizumab continued to exhibit significantly increased OS despite 65% of patients assigned to the chemotherapy arm being allowed to cross over to the pembrolizumab arm. Furthermore, pembrolizumab was associated with less toxicity than chemotherapy, with a manageable long-term safety profile. A durable clinical benefit was observed in patients who completed 35 cycles (2 years) of pembrolizumab, with most patients remaining alive at data cutoff.
Additional studies were documented by Targeted Oncology, and Trialsite News lists the key points below:
- AXL expression has been shown to be involved in cancer invasion, with the potential for the use of protein expression analysis as a biologic marker of tumor progression in patients with lung cancer.
- Bemcentinib is a first-in-class small molecule inhibitor of AXL kinase that has been shown to target the tumor–immune interface to dampen the aggressiveness of cancer cells in vitro and enhance chemotherapy efficacy in murine models.
- The AXL-specific human immunoglobulin G1 antibody conjugated with monomethyl auristatin E (MMAE), enapotamab vedotin (ENA V)11 has demonstrated a primary mechanism of action based on MMAE-mediated killing of AXL-positive tumor cells and AXL-negative bystander tumor cells.
- Previous studies have demonstrated a synergistic effect of antiangiogenic therapy and immunotherapy. A recent phase I trial was the first designed to evaluate a chemotherapy-free regimen combining the PD-1 inhibitor sintilimab with the angiogenesis modulator anlotinib in treatment-naïve patients with advanced NSCLC.
- In a retrospective study of patients with metastatic nonsquamous NSCLC, STK11 and KEAP1 genomic alterations were associated with shorter PFS with frontline chemoimmunotherapy or chemotherapy treatment. Furthermore, STK11 genomic alterations were predictive of inferior clinical outcomes with chemoimmunotherapy in patients with PD-L1–positive tumors.
- Despite heavy interest in its use for predicting outcomes for immunotherapy, TMB has become an elusive biomarker for assessing treatment response in NSCLC, with many investigators striving to incorporate its use into practice with mixed results.
Findings and Advances
Overall, these findings suggest that the selective TMS18 may be a better biomarker for response to immunotherapy than TMB in patients with NSCLC. Additionally, the combination of TMS18 and PD-L1 expression may contribute to improved efficiency for predicting response to immune checkpoint inhibitors; however, validation in larger cohorts is required.23
These advances have contributed to an improved ability for predicting and enhancing responses to immunotherapeutic agents; however, additional questions remain regarding standardization of biomarker measurement and identification of optimal patient subgroups for treatment. Patient subgroups identified as having unmet needs will still require novel therapies and strategies for improved responses to therapy and overall patient outcomes.
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