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).
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.
OncLive: What are the latest data that we have with frontline pembrolizumab and chemotherapy in NSCLC?
: 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.
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.
Can you discuss the IMpower150 data looking at the combination of atezolizumab, bevacizumab, and chemotherapy?
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.