Ramalingam Highlights Immunotherapy Advances in NSCLC

Suresh S. Ramalingam, MD

Recently reported updates from the KEYNOTE-189 and IMpower150 trials demonstrated the powerful impact of adding immunotherapy to treatment regimens for patients with non—small cell lung cancer (NSCLC).

In the phase III KEYNOTE-189 study, the combination of pembrolizumab (Keytruda) with chemotherapy in the frontline setting improved survival in patients with nonsquamous NSCLC. In this trial, which is the confirmatory trial for the FDA approval of pembrolizumab plus carboplatin/pemetrexed, patients received frontline pembrolizumab or placebo combined with pemetrexed and either cisplatin or carboplatin. The study met the primary endpoints of improved overall survival (OS) and progression-free survival (PFS), though full data have yet to be presented.

The IMpower150 trial showed that the addition of atezolizumab (Tecentriq) to bevacizumab (Avastin), carboplatin, and paclitaxel delayed progression or death by 38% compared with bevacizumab and chemotherapy alone for patients with advanced nonsquamous NSCLC (HR, 0.62; 95% CI, 0.52-0.74; P <.0001). There was a 50% reduction in the risk of progression or death with the atezolizumab addition in those patients testing positive for PD-L1 on immune and tumor cells (IHC1/2/3; HR, 0.50; 95% CI, 0.39-0.64).

OncLive: What are the latest data that we have with frontline pembrolizumab and chemotherapy in NSCLC?

In an interview with OncLive, Suresh A. Ramalingam, MD, deputy director of Winship Cancer Institute of Emory University, discussed the exciting findings from the KEYNOTE-189 and IMpower150 immunotherapy trials in patients with NSCLC.Ramalingam: Cohort G of the KEYNOTE-21 trial, which was a randomized phase II study, showed that adding pembrolizumab to chemotherapy in patients with nonsquamous disease was associated with an improved PFS, high response rates, and a trend toward improved survival. That appears to be confirmed by the KEYNOTE-189 study. This has not been formally reported, but we learned from a press release that a large phase III trial that asks the same question in the same group of patients, showed significant improvement in efficacy with the addition of pembrolizumab to chemotherapy in the frontline setting.

This brings the combination approach of chemotherapy plus immunotherapy to the forefront. My view is that we no longer look at all patients with nonsquamous lung cancer as one group in the context of immunotherapy. We need to think about patients who have a high PD-L1 expression of 50%. Then, you have a group of patients who have no PD-L1 expression in the 1% to 50% group. My feeling is that our treatments are going to be defined differently for each of these groups.

For example, we have good data for patients with PD-L1 expression greater than 50%, suggesting that pembrolizumab monotherapy is superior to chemotherapy alone and has a median OS of approximately 30 months in that patient population. Whether chemotherapy plus pembrolizumab is going to be better than pembrolizumab alone is a question for which we still do not know the answer. The KEYNOTE-189 study will give us some hints in that direction.

Can you discuss the IMpower150 data looking at the combination of atezolizumab, bevacizumab, and chemotherapy?

In the 1% to 50% population, chemotherapy plus pembrolizumab may be more attractive because pembrolizumab alone is not commonly used for those patients. When we see the KEYNOTE-189 results and see the PD-L1 expression status, we will have a better sense for which patients should get chemotherapy in combination with immune checkpoint inhibition and which group may be best treated with immunotherapy alone. The IMpower150 study was also a chemotherapy plus a checkpoint inhibition study. The difference here is that patients were treated with carboplatin, paclitaxel, and bevacizumab as the control group. The experimental groups had carboplatin, paclitaxel, and bevacizumab plus atezolizumab. There was a third experimental group with carboplatin, paclitaxel, and atezolizumab alone, but we have not seen the formal results from that comparison.

We know that when compared to chemotherapy plus bevacizumab, the addition of atezolizumab resulted in a significant improvement in PFS. The hazard ratio was 0.6 and the survival results are not mature yet. This was for all nonsquamous patients and those with contraindications to bevacizumab were excluded.

This large trial shows a benefit for adding atezolizumab to carboplatin, paclitaxel, and bevacizumab and also had a biomarker question built in. We showed that the biomarker-positive group had an even better PFS hazard ratio of 0.5. This tells us that the combination treatment is helpful, but the benefits appear to be with the patients with the highest PD-L1 expression status.

Please discuss the status of biomarkers in this setting.

What we need to look at is if you do not have high PD-L1 expression, would you benefit from chemotherapy plus adding an immune checkpoint inhibitor? There results seem somewhat less impressive compared with the highest PD-L1—positive group. The atezolizumab combination with chemotherapy also will belong in the frontline space based on these data and the use in routine clinical practice will depend on the biomarker issue.Biomarkers for immune checkpoint inhibition continue to be developed. PD-L1 expression is farthest along, where we now know that it can be used to select therapy in the frontline setting and even in the second-line setting, as is the case with pembrolizumab.

Can you speak on the progress with liquid biopsies?

Is PD-L1 a perfect biomarker? No. There are many challenges. We do need better markers, whether in substitution of PD-L1 or on top of it. The promising markers seem to be the mutation burden in the tumor looking at T-cell changes in the peripheral blood and so forth. There are studies that are looking at these questions, which will come out in the next year or so where we will have a better understanding of other biomarkers in selection of therapy.Liquid biopsies have been a great addition to the treatment of lung cancer, particularly in patients with oncogene-driven tumors. We now know that if tumor biopsy is not available or is not sufficient to collect molecular testing, you could use liquid biopsies to look for driver mutations. For instance, EGFR mutations can be detected in liquid biopsies. The sensitivity of picking the mutation varies somewhere in the order of 50% to 85% so you cannot substitute a liquid biopsy for tumor biopsy. You can start with the liquid biopsy and if it is positive, you are okay to have more treatments. If it is negative, you still need the tumor.

My approach has always been that, at the time of diagnosis, I rely on tumor biopsies rather than liquid biopsies. However, during the course of treatment when patients develop clinical resistance to targeted therapy, liquid biopsies are helpful. For instance, for EGFR-mutated patients, you need to look for T790M mutations. If it is found in the first liquid biopsy, then we treat them with osimertinib (Tagrisso). If the T790M is not there in the liquid biopsy, then we do the standard biopsy to look for it.

What is your experience with hyperprogression?

The liquid biopsies are now in the first stage of their use. We are going to see more usefulness of liquid biopsies in looking for minimal residual disease, chronically monitoring for acquired resistance emergence, and other important clinical questions as we take care of patients with lung cancer.There have been some reports of hyperprogression, which means that when you start a patient on immune checkpoint inhibition, the tumors start growing faster. I have not seen a large cohort of patients where we can learn from whether this is a true phenomenon or a one-off observation. At this point, if a patient is clinically progressing on immune checkpoint inhibition, most of us would switch the patient to another therapy if treatment options are available. We do not hold on to the immune checkpoint inhibition.

There are ongoing and planned clinical studies that will address the question of whether you continue the immune checkpoint inhibition beyond progression and add a new therapy on top of that or whether you change drugs.

At this point, our clinical recommendations would still be that if a patient has clear progression on checkpoint inhibition you stop and move to a different approach.

Reck M. Primary PFS and safety analyses of a randomized Phase III study of carboplatin + paclitaxel +/− bevacizumab, with or without atezolizumab in 1L non-squamous metastatic NSCLC (IMpower150). Annals of Oncology, 2017;28(11). Abstract LBA1_PR.