Mary E.R. O’Brien, MBBS, Talks Pembrolizumab in Resected Early-Stage Non–Small Cell Lung Cancer by Subgroup

Mary E.R. O’Brien, MBBS, discussed results of an exploratory analysis of the phase 3 PEARLS/KEYNOTE-091 study examining pembrolizumab in resected non–small cell lung cancer.

Results from a subgroup analysis of the phase 3 PEARLS/KEYNOTE-091 trial (NCT02504372) were recently presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting and demonstrated the benefit of adjuvant immunotherapy using pembrolizumab (Keytruda) in the treatment of resected early-stage non–small cell lung cancer (NSCLC).

Mary E.R. O’Brien, MBBS, chair of the Locoregional Disease (LORD) Subgroup of the UK National Cancer Research Institute, medical oncologist at the Royal Marsden Hospital in Sutton, and lead investigator of this study, spoke with CancerNetwork® about how these additional data on the efficacy of pembrolizumab in early-stage NSCLC inform what is already known about immunotherapy in this space.

In this randomized, placebo-controlled, triple-blind study, pembrolizumab significantly improved disease-free survival (DFS) vs placebo in patients with completely resected stage IB (T ≥4cm) to IIIA NSCLC, regardless of PD-L1 expression (n = 1177, HR 0.76, 95% CI, 0.63-0.91, P = 0.0014). Efficacy was demonstrated across all patient subgroups relating to surgery, disease burden, and adjuvant chemotherapy use, and persisted regardless of type of surgery, lymph node involvement, tumor size, or type and extent of adjuvant chemotherapy. Investigators concluded that these data support the efficacy of pembrolizumab following complete tumor resection in NSCLC.

CancerNetwork®: What was the rationale for the PEARLS/KEYNOTE-091 study?

O’Brien: In 2015, data were coming out showing a strong therapeutic effect with the use of immunotherapy in many solid tumors, particularly in lung cancer and melanoma. This was the first time we had seen such a positive signal from a whole new group of drugs. The normal way of drug development is to wait until advanced studies reach maturity and then to slowly move into [larger trials]. Instead we jumped straight [to testing] the effectiveness of these treatments in early-stage NSCLC. This was quite unusual because this process normally takes many years. But [interest grew rapidly] and within a reasonably short time, we had 4 companies with 4 large studies conducted all around the world on the use of immunotherapy after surgery. And now we have results from 2 of those studies, PEARLS/KEYNOTE-091 being one of them. This is a positive study showing that adjuvant immunotherapy [using pembrolizumab] improves outcomes in NSCLC.

What did outcomes look like in the different patient subgroups?

Outcomes in an adjuvant study are different from [outcomes in] studies which examine patients with advanced stages of disease. In those studies, patients still have their tumors and their tumors are causing them to feel poor, so treatments [are administered] to make them feel better, shrink their tumors, and prolong their lives. [Meanwhile], in an adjuvant study [like this], patients’ tumors have been removed and they are normally feeling good. They’re recovering from their surgery. Most of them might not have known for very long that they had cancer. Certainly [after tumor removal], there’s nothing to measure. [In this study], we simply followed and watched patients for relapses, and those were our outcomes. Relapse was our end point. In the past, [recurrence after resection] was a fairly bad outcome and patients often didn’t live very long thereafter. Outcomes are a bit different now, but recurrence after surgery is still a devastating event. That was the end point for the PEARLS/KEYNOTE-091 trial and indeed for all the other trials in this setting.

Now of course, the question becomes: [if relapse occurs], does [pembrolizumab] improve overall survival [OS] vs surgery alone? We generally believe prevention of relapse to be the [best outcome] physically, mentally, socially, socioeconomically, and otherwise because patients can carry on living normal lives. We always try to prevent relapse, and therefore finding whether a treatment prolongs patients’ lives takes a long time. Other medical events like heart attacks [must be accounted for]. OS is our secondary end point. We have been challenged on the basis that it’s not good enough just to prevent relapse; you must [also] prolong life. For this trial, we would have to wait a very long time [for those OS results]. [Therefore], we have reported data at the point in which we can show a significant improvement in time until relapse. [OS data and other data] will follow in due course.

We also had to demonstrate that adjuvant immunotherapy [using pembrolizumab] was safe [and tolerable], and that the adverse effects were manageable. Of course, there are adverse effects to every treatment, and there is always a risk [of serious adverse effects], but this treatment generally behaved as we predicted. Most patients were able to take the entire year of planned treatment. [The safety profile] was satisfactory.

[In summary], the decreased chance of [relapse] is a positive finding from this trial. [Moreover, this result was reproduced with atezolizumab (Tecentriq)] in the IMpower010 trial [NCT02486718]. When you have 2 large trials showing the same thing, you’re hopefully in the right place.

Speaking of adverse effects, did you find anything interesting regarding safety between these patient subgroups?

All patient groups displayed the same safety profile. We didn’t find any risks related to age, type of surgery, or any other common variables. Toxicity, as is often the case, was something we couldn’t predict. In clinical trials, we always try to enroll strong patients in good form, patients without bad hearts or serious medical problems. A clinical trial selects the best of the best or better than the average patient, because you can focus on the cancer. In a trial, however, your entry criteria ensure a very fit patient population and [minimize] unpredictable events. [Of course], there’s always a small risk of random events, but it was nothing severe enough, nothing predictable, and nothing that indicated which patient groups to select or deselect going forward.

Where do you see future research efforts going from here?

We’re still waiting for results from the other 2 major trials and we’ll be examining those subgroups and the data in detail. [However], the next step now is to align this trial and the other adjuvant trials to the CheckMate 816 trial [NCT02998528], which examined patients receiving chemotherapy and immunotherapy before surgery. Ultimately, we have to determine whether it’s better to treat with immunotherapy before surgery or to remove the tumor and treat with immunotherapy afterwards. [Answering that question] will take another randomized study, but at least we now have evidence that it’s best to treat with immunotherapy vs without immunotherapy. In other words, surgery with chemotherapy is inferior to surgery, chemotherapy, and immunotherapy, regardless of whether immunotherapy is given before or after surgery. We just don't yet know which sequence of treatments is best.

What do you hope your colleagues take away from this research?

Overall, we’re probably going to increase the cure rate for lung cancer by another 10%. It took us about 20 years to improve by 5% with chemotherapy. That sounds small, but [that translates into] thousands of patients every year that are cured. Any improvement [in the cure rate] significantly increases the number of lives saved, particularly any improvement over 5%. I think we're going to improve [outcomes] by 10% with this treatment. It will take a few more years to confirm that, but we’re very confident that this treatment decreases the chance of relapse. [This will mean] more patients can carry on with normal, healthy lives looking after their families, paying their taxes, and going to work. This is an important benefit. Additionally, NSCLC is now a disease we can screen for, particularly in smokers and other high-risk patients. Through smoking cessation and screening, we’ll catch lung cancers at earlier stages, and some of those patients with earlier-stage cancers will benefit from in addition to surgery. These are very exciting times for us.


O’Brien MER, 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