KEYNOTE-091 Evaluates Adjuvant Pembrolizumab in Resected Early-Stage NSCLC

In an interview with Targeted Oncology, Mary O’Brien, MD, discussed background of the second interim analysis of the triple-blind, phase 3 PEARLS/KEYNOTE-091 study.

In the triple-blind, phase 3 PEARLS/KEYNOTE-091 study (NCT02504372), pembrolizumab (Keytruda) was shown to improve disease-free survival (DFS) vs placebo in patients with completely resected early-stage non–small cell lung cancer (NSCLC) regardless of surgical resection, tumor size, or the extent of adjuvant chemotherapy.

Data were presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting by Mary E.R. O’Brien, MD.

Within the study, patients with early-stage NSCLC were randomized 1:1 to receive pembrolizumab (n = 590) or placebo (n = 587). Pembrolizumab was administered at 200 mg every 3 weeks for a year while placebo was given at a matching rate. Participants enrolled in the trial were those with pathologically confirmed NSCLC who had previously had surgery, recovered from surgery, or received prior chemotherapy.

Findings revealed that in the patients receiving pembrolizumab as adjuvant therapy, median disease-free survival (DFS) was 53.6 months (95% CI, 39.2-not reached [NR]) vs a median DFS of 42 months for those who were given placebo (95% CI, 31.3-NR; hazard ratio [HR], 0.76; P = .0014). The 18-month DFS rate within the pembrolizumab arm was 73.4% vs 64.3% for patients in the placebo arm. Additionally, 35.9% of patients experienced DFS events with pembrolizumab compared with 44.3% with placebo.

Median DFS for patients in the PD-L1 tumor proportion score of 50% or greater population was not reached, both in the pembrolizumab arm (n = 168) nor the placebo (n = 165) arm (HR, 0.82; 95% CI, 0.57-1.18; P = .14). As for the 18-month DFS rates, the experimental arm had a DFS rate of 71.7% vs 70.1% in the control arm. DFS events were reported in a total of 32.1% of patients within the pembrolizumab arm vs 38.2% of patients in the placebo arm. Within both patient groups, median overall survival (OS) was also not reached (HR, 0.87; 95% CI, 0.67-1.15; P = .17). The 18-month OS rates were 91.7% with those given pembrolizumab and 91.3% with those given placebo.

In regard to safety, nothing unexpected were revealed and grade 3-5 adverse events were reported in a total of 34.1% of patients receiving pembrolizumab as well as in 25.8% of patients receiving placebo.

Overall, the DFS, OS, and safety data reported in this analysis of the PEARLS/KEYNOTE-091 trial support the benefit of pembrolizumab as an adjuvant therapy for patients with stage 1B to stage 3A NSCLC after complete resection.

In an interview with Targeted OncologyTM, O’Brien, Institute of Cancer Research, consultant medical oncologist, and the head of the lung unit at The Royal Marsden NHS Foundation Trust, discussed background of the second interim analysis of the triple-blind, phase 3 PEARLS/KEYNOTE-091 study.

Targeted Oncology: Can you explain the basis for examining pembrolizumab in NSCLC in the KEYNOTE-091 trial?

O’Brien: Normally, when you're developing a drug and its traditional, particularly with cancer, you always give the drug to the disease when it's most advanced, because first of all, those patients need it most, and therefore are prepared to take more risks. You initially get a feel of whether your drug could be active in that situation. Then as you see if the drug might be doing something, it could maybe do more if the disease wasn't so advanced, so you keep moving it forward.

This drug [pembrolizumab] has already been used by itself with chemotherapy with radiotherapy in third line, in second line, and in first line, advanced disease. Now, we're moving into early patients, some of whom have already been cured by their surgery and seeing if we can cure more after surgery. There has been an evolution, but in general, most of the indications and most of the diseases that have been in trial with pembrolizumab have shown that this is a drug that has broad, positive benefits for patients.

What did you present regarding the study at ASCO 2022?

O’Brien: At ASCO, I presented a study called KEYNOTE-091, also called the PEARLS trial. This is a study in patients with lung cancer who have had surgery, have had their lung cancer removed, have recovered from their surgery, and have had a course of chemotherapy, which is what we would normally do, and then, they've gone into the trial. They've been randomized to either receive 1 year of 3 weekly injections with pembrolizumab, or 1 year of 3 weekly injections with a placebo. They've been followed over at least 3 years to see if their cancer has been controlled, has it come back, have they died, their toxicities, etc.

Can you explain some of the key points of the second interim analysis of the trial?

After 3 years, we've compared the group who got the pembrolizumab to the group that got the placebo. Overall, the trial is a positive trial in that it showed that the use of pembrolizumab did decrease the time it takes for the disease to come back, was well tolerated, and appeared to have helped most people live longer without their disease coming back than the placebo. It is a positive trial overall. For the purpose of this ASCO poster and discussion, we have represented this overall information on disease-free survival, and overall survival. We have also looked at more subgroups, looking at details of the type of surgery that they had, whether lymph nodes were involved or not, the sort of chemotherapy they had after the surgery, and to see if any other factors were imbalanced or may explain some of the differences.

What were some of the findings of the study?

It doesn't matter what these factors were. The patients who got the treatment still had a better outcome than those who didn't. To translate that into the real world, it means that we now have an extra treatment for patients after surgery and chemotherapy, which would involve this drug for a year. That does increase their chances of living a longer and better life without their disease coming back. That's the new finding and it will mean for many people, a paradigm shift in the way they're treated.

What would you consider to be the main unmet needs in the NSCLC space?

In general, we think about it as that when a patient goes into surgery, they come out of their surgery, and about half of them will have been cured already. But of course, that means half of them will not have been cured. We give chemotherapy, and we cure another 5%. My feeling is that with this immunotherapy, that in general will probably add another 10% to that. That takes us up overall to about 65% of our patients with this combined effort. That means still 35% will not be cured, and 1 in 3 patients are still the unmet need. The job's not done yet and we are not curing all our patients.

We still have to do more trials. I think what this trial has taught us is that we must be more courageous [as it can be] hard to cure, so we must keep trying and we must do these studies after surgery early on and when a drug is coming out and being developed. [We can] not wait for years of the drug being used and advanced disease, we must get in quickly. This trial and 1 other are the first 2 trials in this early stage with immunotherapy in lung cancer. It has been great to have companies to buy into this approach and not to be afraid. It's also been great for patients to have agreed to go along with our logic to put themselves forward and to take part in the trial. As always, it is the patient going into the trial that helps us doctors make the progress, which then goes back to them, but it takes everybody to play ball.

What is still needed to help lead us to breakthroughs in research for NSCLC?

It is all about science and biology. It's all about finding targets and finding pathways that have caused cancer and are driving tumors, whether those pathways are by chemicals or by the immune system, or by something else that we really don't know yet. Thirty years of science translates into these years of the progress we're making. It will be the ongoing science and the next round of trials that will be the next way forward.

We have to keep trying to find biology and new explanations. Then once we know what else has gone wrong, we can target, and we develop drugs. That's why we work and that all continues. It's hard because so much of science is negative, doesn't produce targets, costs a lot of money and a lot of effort, and a lot of patient effort, and sometimes toxicities. Occasionally we do get lucky, and we do make breakthroughs.

What key points do you recommend community oncologists take away from your research?

The paper is going to make changes and will be published. I don't think it's going to be too difficult for community oncologists because they have been using these drugs already in advanced patients, and therefore they know their toxicity. But the risks are a little bit higher, and potentially, you are going to feel worse about toxicity. It does require careful monitoring and attention to detail. I do think we have acquired those skills and I think this treatment will be widely taken up by all oncologists, as we have already a great experience managing this drug and the situation.

O'Brien M, Paz-Ares L, Jha N, et al. EORTC-1416-LCG/ETOP 8-15 – PEARLS/KEYNOTE-091 study of pembrolizumab versus placebo for completely resected early-stage non-small cell lung cancer (NSCLC): outcomes in subgroups related to surgery, disease burden, and adjuvant chemotherapy use. J Clin Oncol. 2022;40 (suppl 16): 8512). doi:10.1200/JCO.2022.40.16_suppl.8512