Expert Examines Emerging Biomarkers in NSCLC

Brandon Weckbaugh, MD

The treatment landscape of non—small cell lung cancer (NSCLC) continues to expand with potential biomarkers that are under investigation, as well as novel agents that could potentially target them. What was once a major area of unmet need has experienced an explosion of new research, said Brandon Weckbaugh, MD.

“In NSCLC, when a patient is diagnosed with metastatic NSCLC, we will check for actionable mutations,” said Weckbaugh. “Currently, there are EGFR, ROS1, and ALK—to give a few examples. But there are a few emerging biomarkers for which there are newly approved, or likely soon-to-be approved, drugs that are able to target these mutations.”

Beyond EGFR, ROS1, and ALK, are RET, HER2, and NTRK, according to Weckbaugh, and some of these biomarkers already have targeted drugs approved for them. For example, with regards to RET, the FDA granted LOXO-292 a breakthrough therapy designation in September 2018 as a treatment for patients with advanced RET fusion—positive NSCLC based on data from the phase I LIBRETTO-001 trial, which showed an objective response rate of 77% (95% CI, 58%-90%) in this patient population.¹

In terms of NTRK, in November 2018, the FDA approved larotrectinib (Vitrakvi) for adult and pediatric patients with solid tumors that have NTRK gene fusions without a known acquired resistance mutation. Furthermore, the FDA granted a breakthrough therapy designation to entrectinib in May 2017 for the treatment of adult and pediatric patients with NTRK-positive, locally advanced or metastatic solid tumors who have either progressed following prior therapies or who have no acceptable standard treatments.

Tumor mutational burden (TMB) is also being explored as a potential biomarker in NSCLC. One study published in 2017 examined the relationship between TMB and outcome in several cancers treated with various immunotherapies. For the study, a total of 151 patients treated with immunotherapy were assessed for response rate, progression-free survival (PFS), and overall survival (OS). Higher TMB was linked with better outcome parameters.²

The response rate for patients with high TMB (≥20 mutations/megabase [mb]) versus low-to-intermediate TMB was 58% (22/38) compared with 20% (23/113; P = .0001). Median PFS was 12.8 months in those with high TMB compared with 3.3 months in those with low-to-intermediate TMB (P ≤.0001), while the median OS was not reached versus 16.3 months (P = .0036).

Results were found to be similar when single agent PD-1/PD-L1 inhibitors were analyzed in 102 patients. Investigators observed a linear correlation between higher TMB and favorable outcome parameters. The median TMB for responders versus nonresponders treated with anti—PD-1/PD-L1 monotherapy was 18.0 compared with 5.0 mutations/mb (P < 0.0001).

OncLive: What drugs have recently been approved for some emerging biomarkers in NSCLC?

Could you discuss tumor mutational burden (TMB) and how it’s being investigated as a potential biomarker?

In an interview during the 2018 OncLive^® State of the Science Summit^TM on Advanced Non—Small Cell Lung Cancer, Weckbaugh, an oncology fellow at the University of Missouri-Kansas City, shed light on emerging biomarkers in NSCLC.Weckbaugh: Previously, this was an area of unmet need with actionable mutations in NSCLC. But more recently, there have been a couple of new drugs approved, which are targeted for some of these mutations. To take NTRK as an example, there are 2 drugs that have [shown promise]—entrectinib and larotrectinib. These have shown very good efficacy and responsiveness for patients with NTRK-mutated NSCLC, which is important because NTRK is mutually exclusive with other oncogenic drivers. This is why I say this is an area of unmet need for targetable therapies.Previously, when we were diagnosing metastatic NSCLC, one of the markers to check was PD-1/PD-L1 expression of the tumor. There have been times when that has been a little bit frustrating, as it is not a perfect predictor of how the patient is going to respond to therapy. By using TMB, the theory was that this would increase the immunogenicity of the patient's tumors.

Were there any other clinical trials that you wanted to highlight?

Where do you see research headed?

In a study where they looked at 151 patients—36 of which were patients with lung cancer—who underwent next-generation sequencing (NGS) and then subsequently received immunotherapy with anti—PD-1/–PD-L1 inhibitors, when they looked at the patients with high or intermediate TMB versus low TMB, the trend was that more tumor mutations present correlated with improved progression-free survival with immunotherapy.One trial that I discussed at [the meeting] is the LIBRETTO-001 trial, which is a trial studying the use of LOXO-292, a TKI targeting the RET mutation. [Data from] this trial showed some very good responsiveness in RET fusion mutation-driven cancers that were really irrespective of the RET fusion partner, as well as whether patients had received prior kinase inhibitor therapy or if they were naïve to prior therapy.One thing that will be interesting to follow up on in the future is, as it pertains to NTRK mutations, there are a few other second-generation investigational NTRK inhibitors, such as LOXO-195. This agent is being studied to look at tumors with an acquired or baseline resistance mutation to larotrectinib, so the data will be interesting to see as that emerges.

In terms of TMB, it will be interesting to see, as the data mature, and as more and more patients are undergoing NGS, to see if what we're seeing in the trial by Aaron M. Goodman, MD, and colleagues if that will continue in the future—where there is a correlation between higher TMB and increase in PFS for patients receiving PD-1/PD-L1 inhibition. Those [data will] be interesting to see.

References

1. Drilon AE, Subbiah V, Oxnard GR, et al. A phase 1 study of LOXO-292, a potent and highly selective RET inhibitor, in patients with RET-altered cancers. J Clin Oncol. 2018;36(suppl; abstr 102).
2. Goodman AM, Kato S, Bazhenova L, et al. Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers. Mol Cancer Ther. 2017;16(11):2598-2608. doi: 10.1158/1535-7163.MCT-17-0386.