Ari VanderWalde, MD
The rationale behind combining chemotherapy with immunotherapy in non–small cell lung cancer (NSCLC) is perplexing to Ari VanderWalde, MD, as he says findings from 2 pivotal trials in the last year—KEYNOTE-021 and IMpower150—may not be fully applicable to the current landscape.
Findings from cohort G of the phase II KEYNOTE-021 trial led the FDA to grant an approval to the frontline treatment of pembrolizumab (Keytruda) plus pemetrexed and carboplatin in patients with nonsquamous NSCLC regardless of PD-L1 expression in May 2017.1
Investigators reported that the median progression-free survival (PFS) was 13.0 months with the addition of pembrolizumab versus 8.9 months for chemotherapy alone (HR, 0.53; 95% CI, 0.31-0.91; P
In IMpower150, immunotherapy plus chemotherapy and bevacizumab was compared with chemotherapy alone. Findings showed that the addition of atezolizumab (Tecentriq) to bevacizumab (Avastin), carboplatin, and paclitaxel delayed progression or death by 38% versus bevacizumab and chemotherapy alone for patients with advanced nonsquamous NSCLC.2
In a presentation during the 2018 OncLive®
State of the Science Summit™ on Advanced Non–Small Cell Lung Cancer, VanderWalde cautioned community oncologists about using these trials as a basis for treatment decisions, as they were initiated before the establishment of pembrolizumab as a frontline standard of care for patients with NSCLC who have PD-L1 expression over 50%.
“Recognize that putting patients on clinical trials is still the best way to take care of these patients with lung cancer,” said VanderWalde. “Deferring to what the FDA has approved is not necessarily the right answer. We don’t know what the right answer is. Trying to figure out the answers to these questions will hopefully keep us busy for some amount of time.”
VanderWalde, director of clinical research at West Cancer Center, associate vice chancellor of clinical research at the University of Tennessee Health Science Center, explained his trepidation with these combinations of chemotherapy and immunotherapy in an interview during the meeting.
OncLive: Can you provide an overview of your presentation?
Combining immunotherapy with other immunotherapy, or with chemotherapy, is a rapidly developing field. The strategy of combining immunotherapies together has been under study for some time, but the large studies have not come out yet. I focused my talk on combining immunotherapy with chemotherapy, particularly in the frontline space. I limited my talk to the 2 large pieces of data that have been presented, but they are 2 very confusing studies. These are studies that have led to the FDA approval, which I argued might not be fully warranted with the current data.
The first study was a phase II study published [in 2017] called KEYNOTE-021. It was a 120-patient study of patients with NSCLC, generally adenocarcinoma, and they were given either the combination of the PD-1 inhibitor pembrolizumab in combination with carboplatin and pemetrexed, or they were given carboplatin and pemetrexed alone. Anyone with NSCLC who fit the criteria was allowed in. What it showed was that the PFS was clearly better for the patients who received the combination as opposed to chemotherapy alone.
The second study I discussed was the IMpower150 study, which is a slightly more complicated study. It combined the PD-L1 inhibitor atezolizumab plus the VEGFR inhibitor bevacizumab together with carboplatin and paclitaxel. It compared that regimen with patients receiving bevacizumab, carboplatin, and paclitaxel. This was a much larger study as it had 1200 patients. It showed that the combination of all 4 agents was better than the combination of bevacizumab, carboplatin, and paclitaxel.
The traditional interpretation of these studies is that, because they showed a benefit in the general population that they studied, combinations are better than anything else that we have available. What was not taken into account though was that, during the course of the studies, frontline lung cancer became segmented based on PD-L1 status.
For those who had a PD-L1 expression greater than 50%, the standard is no longer chemotherapy or chemotherapy plus bevacizumab—the standard has now become single-agent pembrolizumab. Both of these studies included quite a number of patients in each arm and compared combinations with chemotherapy and, knowing what we know now, they should have compared it with immunotherapy alone.