Lead Investigator Discusses Frontline Pembrolizumab in NSCLC

Gilberto Lopes, MD

Results from the phase III KEYNOTE-042 trial demonstrated an improvement in overall survival (OS) with single-agent pembrolizumab (Keytruda) versus chemotherapy as a frontline treatment for patients with locally advanced or metastatic non—small cell lung cancer (NSCLC) and a PD-L1 expression level ≥1%, emphasizing immunotherapy’s role in the treatment armamentarium.

“This trial is very important because it included both patients with squamous and nonsquamous NSCLC,” said lead author Gilberto Lopes, MD. “This a broader population, and the trial shows the benefit of pembrolizumab and immunotherapy in general in this patient population.”

In KEYNOTE-042, the median OS was 16.7 months with frontline pembrolizumab monotherapy compared with 12.1 months with standard chemotherapy in patients with advanced or metastatic NSCLC and a PD-L1 tumor proportion score (TPS) ≥1% (HR, 0.81; 95% CI, 0.71-0.93; P = .0018). Across all patients with a PD-L1 TPS of 1% to 49%, which was an exploratory analysis, the median OS was 13.4 months with pembrolizumab compared with 12.1 months for chemotherapy (HR, 0.92; 95% CI, 0.77-1.11).

The OS benefit for pembrolizumab correlated with greater levels of PD-L1 expression: TPS ≥50% (20 vs 12.2 months; HR, 0.69; 95% CI, 0.56-0.85; P = .0003); TPS ≥20% (17.7 vs 13.0 months; HR, 0.77; 95% CI, 0.64-0.92; P = .002); and TPS ≥1% (16.7 vs 12.1 months; HR, 0.81; 95% CI, 0.71-0.93; P = .0018).

Based on these results, the FDA granted a priority review designation to a supplemental biologics license application for the PD-1 inhibitor in September 2018. If approved, pembrolizumab’s label would be expanded to include frontline treatment for patients with NSCLC and a tumor proportion score (TPS) ≥1% whose tumors do not harbor EGFR or ALK genomic aberrations. The FDA is scheduled to decide on the application by January 11, 2019.

OncLive: What was the rationale and background of the KEYNOTE-042 trial?

In an interview with OncLive^®, Lopes, a medical oncologist at Sylvester Comprehensive Cancer Center, University of Miami Health System, discussed the KEYNOTE-042 results and ongoing developments with immunotherapy in NSCLC.Lopes: The way we treat lung cancer has changed markedly over the last few years. Some days, it feels like it's changing hour to hour. We have developed new targeted agents for patients with EGFR mutations and ALK translocations, as well as for those with other genetic changes. Immunotherapies have become part of our standard armamentarium. Pembrolizumab, in particular, is a PD-1 inhibitor that has been tested in a number of different clinical scenarios.

In KEYNOTE-010, it was shown to be better than chemotherapy with docetaxel for patients who had failed first-line chemotherapy. It was also better than chemotherapy as a single agent for patients with a PD-L1 expression of 50% and above. In combination, it was also shown to be better than chemotherapy for patients with any level of PD-1 expression and without any PD-L1 expression.

KEYNOTE-042 was a study that was set up a number of years ago to assess the efficacy of pembrolizumab versus standard chemotherapy for patients with PD-L1 expression with a TPS of ≥1%. This was a trial designed for patients with nonsquamous and squamous histology. Patients had to have a good performance status of 0 or 1, and they could not have EGFR mutations or ALK translocations. Our primary endpoint was OS. OS was to be tested sequentially in patients with a TPS ≥50%, ≥20%, and ≥1%.

The primary endpoint was positive. OS was better for all patients in the trial, including patients with a TPS ≥1%. For that specific patient population, we had an HR of 0.81 and a P value of .0018. In addition, we also tested for progression-free survival (PFS) as a key secondary endpoint. That was also supposed to be tested for the ≥50% population first. Even though it did fine with a HR of around 0.8, the P value of .0019 was not low enough for the interim analysis, especially for it to be crossed. As such, the PFS was not positive in the interim analysis. Because of that, we did not have statistical testing for PFS for the other subgroups.

The results for response rates were quite similar between pembrolizumab and chemotherapy. [Pembrolizumab was favored in that] the durations of responses were much longer. The duration of response with pembrolizumab was 20 months and ranged between 8 and 9 months with chemotherapy.

Moreover, patients who received pembrolizumab had fewer adverse events (AEs). Seventeen to 18% of patients had treatment-related AEs that were graded 3 to 5 with pembrolizumab. Approximately 41% of patients had the same type of AEs with chemotherapy. Of course, immune-mediated AEs were more common with pembrolizumab than with chemotherapy.

Overall, this is the largest study with 1274 patients to test pembrolizumab as a single agent versus chemotherapy as a single modality. The study confirmed that pembrolizumab is an option for patients with a TPS expression of ≥1%. We now have to place that in perspective with other studies. We have combinations of chemotherapy and immunotherapy that improve survival versus chemotherapy.

My clinical impression is that patients with a large volume of disease or symptomatic disease should consider combinations of chemotherapy and immunotherapy. Patients with lower volume of disease and those who have higher levels of PD-L1 expression are patients for whom we might consider pembrolizumab as a single agent.

What safety considerations should we be aware of?

We will continue to evaluate the data from our trial. We are going to do an indirect meta-analysis comparing some of the KEYNOTE trials. We hope that will bring us more information, so we can truly select the patients who will benefit the most from immunotherapy or from the combination of chemotherapy and immunotherapy. We'll have a lot more to talk about once we come to the 2018 ESMO Congress.Our median follow-up was 12.8 months, so we only have midterm toxicity in our patient population. When we look at trials with pembrolizumab and other immune checkpoint inhibitors, the drugs tend to be very safe. Of course, we need to learn how to manage immune-mediated AEs, but once we do it's usually very safe.

Though the trial didn't include patients with EGFR and ALK abnormalities, are there scenarios in which giving immunotherapy to these patients is appropriate?

We see very few deaths from the use of pembrolizumab. In our trial, 637 patients were treated with pembrolizumab. There was 1 death that was attributable to pneumonitis. That patient also had progression of disease, so we classified it as a treatment-related AE. We are not 100% sure that this was not progression. That's something that happens in clinic often, so we have to be very aggressive with management of immune-mediated AEs.It’s still an open question. There were a number of studies at the 2018 ASCO Annual Meeting suggesting that there may be some populations [who could benefit]. One thing is for sure: we should not use immunotherapy as a first-line treatment for these patients. They should have failed every single option that they have before we entertain the possibility of using immunotherapy.

How do you decide who is best suited to receive immunotherapy?

We're trying to learn whether the combination of immunotherapy and chemotherapy might be the best option for those with driver mutations. There is no option that has been endorsed by any guidelines or that has been approved by the FDA. It's important to note that patients with EGFR mutations or ALK translocations, even if they have a high PD-L1 expression, do not seem to respond well to an immune checkpoint monotherapy.We need better ways of selecting which patients benefit the most from immunotherapy. We know that patients who respond to immunotherapy have very long durations of response, but not every patient responds. The majority of patients do not respond to single-agent immunotherapy. Much work has been done with PD-L1 but it is not a perfect biomarker.

Tumor mutational burden (TMB) is also being developed as a biomarker. We now have at least one large phase III trial suggesting some PFS benefit with the combination of the CTLA-4 and PD-1 inhibitors ipilimumab (Yervoy) and nivolumab (Opdivo). We have a lot more work to do for validation, and we certainly need to find other biomarkers because neither PD-L1 nor TMB are perfect.

Lopes G, Wu YL, Kudaba I, et al. Pembrolizumab (pembro) versus platinum-based chemotherapy (chemo) as first-line therapy for advanced/metastatic NSCLC with a PD-L1 tumor proportion score (TPS) ≥ 1%: open-label, phase 3 KEYNOTE-042 study. J Clin Oncol. 2018;36 (suppl; abstr LBA4).