Hellmann Expands on TMB Testing in Lung Cancer

Matthew D. Hellmann, MD

PD-L1 and the recent emergence of tumor mutational burden (TMB) have helped guide physicians in selecting appropriate immunotherapy agents for patients with non—small cell lung cancer (NSCLC). Although the biomarkers are independent of each other, they have enabled practitioners to further predict the benefit of these therapies, explains Matthew D. Hellmann, MD.

An updated analysis of the CheckMate-586 study, which was presented during the 2018 AACR Annual Meeting, found that TMB identified patients who were more likely to derive a benefit from frontline combination immunotherapy with nivolumab (Opdivo) and ipilimumab (Yervoy).¹ The study assessed the frontline combination for up to 2 years in patients with advanced NSCLC. The primary endpoint was overall response rate (ORR), stratified for patients with a PD-L1 expression less than or greater than 1%.

Results showed that the combination induced an ORR of 30%. Additionally, patients who presented with PD-L1 expression greater than 1% had an ORR of 41% versus 15% in those patients with less than 1% expression. Patients who were stratified by TMB showed response rates of 9% with TMB less than 5, 15% with TMB 5 to 10, 44% with TMB ≥10, and 39% for those with TMB levels of ≥15.

The implication of TMB on response rates was mirrored in the phase III results of the CheckMate-227 trial, in which the combination of nivolumab and ipilimumab more than tripled the 1-year progression-free survival (PFS) rate versus chemotherapy for treatment-naïve patients with NSCLC with high TMB.^2,3 The 1-year PFS rate was 43% for patients with TMB ≥10 mutations/megabase treated with the immunotherapy combination versus 13% in those treated with platinum-doublet chemotherapy. The median PFS was 7.2 months versus 5.5 months, respectively. The investigators reported a significant reduction in risk of disease progression or death of 42% (HR, 0.58; 97.5% CI, 0.41-0.81; P <.001).

“Both of these biomarkers allow us to give immunotherapy to the right people and, in essence, avoid the toxicity of chemotherapy and have the opportunity for durable responses,” said Hellmann. “Should they need it, patients still have chemotherapy as a second-line therapy.”

OncLive: Please provide an overview of your presentation at the meeting.

In an interview during the 2018 OncLive^® State of the Science Summit™ on Advanced Non—Small Cell Lung Cancer, Hellman, an assistant attending physician at Memorial Sloan Kettering Cancer Center, discussed the expansion of these biomarkers across single-agent and combination therapies in patients with NSCLC.Hellmann: One of the things that was discussed was the progress we've made in understanding who best benefits from immunotherapy. We have known about the opportunity for immunotherapy and the possibility of long-term outcomes that are not possible with other treatments in lung cancer for a long time, and that’s really given patients hope. I have a handful of patients who are doing well years after they started immunotherapy. That possibility didn't exist prior to immunotherapy, so it's been a huge breakthrough. However, only a small fraction of patients who receive immunotherapy have an exceptional benefit.

It's important to understand who those patients are and how we can identify them beforehand—how we can predict who is the most likely to benefit from the therapy. The first biomarker that has come onto the clinical scene is PD-L1, based on studies such as KEYNOTE-024. PD-L1 has an important role in the management of patients with lung cancer and should be tested in all patients with lung cancer to determine whether frontline checkpoint inhibitor monotherapy is appropriate.

Is TMB a predictive or prognostic factor?

TMB is an emerging biomarker that is independent of PD-L1 and represents a new group of patients who can benefit from immunotherapy. We've made important progress in terms of identifying precision markers for use in immunotherapy.When I first talked about TMB as a biomarker, it was largely in studies of patients in single-arm studies. People were uncertain about whether TMB was truly identifying predictive markers, or whether it was just identifying patients who happened to live longer.

How does TMB factor into determining combination therapies?

Emerging data have really clarified that it is a predictive marker. Randomized studies of patients treated with PD-1 monotherapy or chemotherapy showed that only those patients who received PD-1 therapy had improvement, based on TMB. Patients who were randomized to chemotherapy showed no difference. Studies like those have highlighted that [TMB] is truly a predictive marker. When we first looked at TMB as a biomarker, we focused on patients treated with PD-1 monotherapy. There was uncertainty about whether or not the same sort of correlation would be seen in patients who received combination immunotherapy. We wondered whether the additional immunotherapy agent might broaden the immune response that occurred and consequently diminish the importance of TMB.

Are there any clinical trials looking at acquired resistance to immunotherapy?

However, the opposite is true in patients with both NSCLC and small cell lung cancer. TMB may matter even more in patients treated with combination immunotherapy. It has been a successful biomarker, particularly in patients treated with combination immunotherapy. A lot of individual centers are trying to maximize the amount of information we can learn from patients who develop acquired resistance. There is not a specific clinical trial that is exploring mechanisms of acquired resistance, but that's a real study of importance for many investigators.

Can you expand more on the process of TMB testing?

Of course, there are lot of clinical trials for patients who have, unfortunately, not responded as well as we hoped they would on [checkpoint inhibitor] monotherapy. That is a huge opportunity for clinical development of next-generation immunotherapies. TMB might sound as if it's a separate test; however, this is additional data we get from the routine molecular analysis that we should be doing in all patients with lung cancer.

When we think about lung cancer, we have increasingly started to visualize the disease as a pie chart in which patients are defined by their distinct biology. EGFR, ALK, RET, ROS1, and BRAF are all examples of identified molecular markers that [are targeted to] specific therapies for those patients. Molecular profiling has enabled us to understand these aberrations and TMB. This ultimately brings a new piece of the pie that contains specific therapy indications with exceptional opportunity for long-term benefit.

References

1. Ramalingam S, Hellmann MD, Awad M, et al. Tumor mutational burden (TMB) as a biomarker for clinical benefit from dual immune checkpoint blockade with nivolumab (nivo) + ipilimumab (ipi) in first-line (1L) non-small cell lung cancer (NSCLC): identification of TMB cutoff from CheckMate 568. In: Proceedings from the 2018 AACR Annual Meeting; April 14-18, 2018; Chicago, Illinois. Abstract CT078. www.abstractsonline.com/pp8/#!/4562/presentation/11131.
2. Hellman MD, Ciuleanu T, Pluzanski A, et al. Nivolumab (nivo) + ipilimumab (ipi) vs platinum-doublet chemotherapy (PT-DC) as first-line (1L) treatment (tx) for advanced non-small cell lung cancer (NSCLC): initial results from CheckMate 227. In: Proceedings from the 2018 AACR Annual Meeting; April 14-18, 2018; Chicago, Illinois. Abstract CT077.
3. Hellman MD, Ciuleanu T, Pluzanski A, et al. Nivolumab plus ipilimumab in lung cancer with a high tumor mutational burden [published online April 16, 2018]. N Engl J Med. doi: 10.1056/NEJMoa1801946.