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Edward B. Garon, MD, MS, highlights the 5-year KEYNOTE-001 data and also the activity with lurbinectedin in small cell lung cancer.
Edward B. Garon, MD
Five-year follow-up data of the phase Ib KEYNOTE-001 trial showed that pembrolizumab (Keytruda) led to an overall survival (OS) rate of 23.2% in treatment-naïve patients and 15.5% in previously treated patients with non—small cell lung cancer (NSCLC) as opposed to the historical 5%, explained Edward B. Garon, MD, MS.
The KEYNOTE-001 trial enrolled 550 patients with locally advanced or metastatic NSCLC and treated them with pembrolizumab.1 Patients were stratified into previously treated (n = 449) or treatment naïve (n = 101) cohorts. At a median follow-up of 60.6 months, 82% of participants had died. The investigator-assessed overall response rate (ORR) was 42% in treatment-naïve patients and 23% in previously treated patients. The median duration of response was 16.8 months for untreated patients and 38.9 months in those who received prior treatment.
“The clinical implications [of the KEYNOTE-001 trial] are that advanced NSCLC is not exactly what it has traditionally been,” said Garon, associate professor of medicine at the David Geffen School of Medicine at the University of California, Los Angeles. “Although it is a situation where there are many patients who don't derive much benefit from therapy, now is there is a sizable group of patients who experience the promise of immunotherapy with long, durable responses leading often fairly normal lives even many years after their diagnoses.”
In small cell lung cancer (SCLC), however, novel agents are showing encouraging data. In a single-arm, phase II study, single-agent lurbinectedin elicited a 35.2% ORR and a 68.6% disease control rate in patients with SCLC who had a median of 1 prior treatment.2 In August 2019, it was announced that a new drug application will be submitted in late 2020 to the FDA under accelerated approval status for lurbinectedin as a second-line treatment of patients with SCLC.
In an interview with OncLive, Garon highlighted the 5-year KEYNOTE-001 data and also the activity with lurbinectedin in SCLC.
OncLive: Could you give an overview of pembrolizumab in the NSCLC setting?
Garon: Pembrolizumab now has several different approvals in NSCLC. It is approved as a monotherapy for patients who are PD-L1-positive in previously treated and treatment-naïve settings. In addition, it is approved in combination with chemotherapy consisting of carboplatin and pemetrexed in patients with nonsquamous NSCLC. Pembrolizumab can also be combined with carboplatin/paclitaxel—either traditional paclitaxel or nab-paclitaxel—in patients who have squamous cell carcinoma of the lung.
Could you discuss the phase Ib KEYNOTE-001 trial and the data that were presented?
KEYNOTE-001 was the original study of pembrolizumab. However, it was not typical of first-in-human studies because it enrolled over 1000 patients and led to the initial approvals in melanoma and NSCLC, as well as approval of an assay to look at PD-L1 expression. As part of that original study, it was shown that we had an ORR of about 20%, which was even higher in treatment-naïve patients. It was also shown that the clinical benefit appeared to correlate quite well with PD-L1 expression, particularly with the best outcomes being amongst patients who had PD-L1 expression in at least half of their tumor cells.
What were the 5-year findings of this trial?
It’s not as surprising from where we sit today, having seen the development over the last several years, but it is surprising when one takes into account where the field was when we first started this study in 2012. We were able to show that we had a significant 5-year OS rate among patients with advanced NSCLC. Prior to the publication, we would have anticipated a 5-year OS rate for advanced NSCLC somewhere around the 5% range. The study found that over 15% of patients were alive at 5 years.
The study was divided into 101 patients who were treatment naïve and another 449 patients who had received prior therapy. In the treatment-naïve group, it was an even higher 5-year OS rate of over 20%. When one looks specifically at the patients who had PD-L1 expression in at least half of their cells, at least one quarter of patients in both groups [were alive at 5 years].
We also updated the safety, which was last updated at the 3-year mark. There were a few events, but it was very rare to have toxicity between the 3-year follow-up and 5-year follow-up.
Where should future research focus next for NSCLC treatment?
There have already been efforts of combination therapy. To date, combinations of a PD-1 or PD-L1 inhibitor, along with approved approaches such as chemotherapy and/or radiation, have shown some evidence of benefit. It has been a little harder in specifically immunotherapy combinations. That is something that [researchers] will continue to work on in terms of combinations.
Refining biomarkers and seeing if we can add to the value of PD-L1 expression [needs to be addressed]. It is important to figure out how to identify patients who had a 50% chance of 5-year OS, because this would help patients make decisions about how they want to manage their care.
Moving on to SCLC, could you give an overview of developments in this space?
There are a few advances in that space. There was the approval of atezolizumab (Tecentriq) with frontline chemotherapy, which has been the most significant of the recent frontline data; there was an improvement in OS. This is in a disease where we've seen very little change in the standard of care in the last several decades. That's a very significant change and the adoption of that is quite significant.
There also was an approval of nivolumab (Opdivo) in the third-line setting after platinum-based chemotherapy and then subsequent topotecan. The role of that approval is still a little unclear in an era where atezolizumab is an approved agent in the frontline setting. We do not know if the patients who progressed on chemotherapy plus atezolizumab will respond to nivolumab in the third-line setting.
There were also data presented at this meeting about lurbinectedin, which functions similarly to a cytotoxic type of approach, showing a real response rate in that setting. How that compares with topotecan is an area that will be further explored, but it is encouraging to see new developments in SCLC, which has been a particularly difficult disease for long periods of time.
Could you expand on the research with lurbinectedin?
There was a group of patients with clearly deriving benefit and an expected toxicity profile. It was an agent that has been evaluated previously and the safety signals that were seen were in line with what would have been expected from the agent.