Frontline Pembrolizumab Bests Chemo in NSCLC, Especially in PD-L1-High Subgroup

Gilberto Lopes, MD

Patients with non—small cell lung cancer (NSCLC) treated with frontline pembrolizumab (Keytruda) lived 4 to 8 months longer than those who received standard of care chemotherapy, depending on their level of PD-L1 expression, according to results from the KEYNOTE-042 study presented at the 2018 ASCO Annual Meeting.

In the phase III trial, overall survival (OS) was correlated with greater levels of PD-L1 expression: Tumor proportion score (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) compared with chemotherapy.

Across all patients with 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; 0.77-1.11).

“Pembrolizumab becomes an option for patients who have advanced non-small cell lung cancer and do not have EGFR or ALK mutations, and who do express PD-L1 at at least the 1% level,” said lead study author Gilberto Lopes, MD, MBA, a medical oncologist at the Sylvester Comprehensive Cancer Center, University of Miami Health System in Florida. “We do need to do a lot more work. Even though patients do better today, they still do not do well enough. The vast majority of patients with advanced lung cancer will have disease progression and will succumb to lung cancer. So, we need to continue doing more work.”

Chemotherapy has been the standard of care for patients with NSCLC who do not have driver mutations; however, in a previous study, KEYNOTE-024, pembrolizumab significantly improved progression-free survival (PFS) and OS compared with chemotherapy as a first-line treatment for metastatic NSCLC, in patients without targetable alterations with a PD-L1 TPS of ≥50%, leading to FDA approval.

“What we have seen over the last few years is that a combination of new agents, including targeted agents and immunotherapies, have helped patients live a little longer, but we still have a lot of effort and work to do,” added Lopes.

In the large, randomized phase III trial, which the researchers highlighted to be the largest clinical trial of pembrolizumab as a standalone therapy, 1274 patients with locally advanced or metastatic NSCLC were randomized to pembrolizumab or chemotherapy with paclitaxel plus carboplatin or pemetrexed plus carboplatin. The researchers made note that both squamous and non-squamous cancers were included, but not cancers with genetic changes that could be treated with targeted therapies such as EGFR and ALK inhibitors.

Patients were separated into 3 arms according to TPS: ≥50% (n = 599), ≥20% (n = 818), and ≥1% (n = 1274). An equal number of patients in each PD-L1 expression group received pembrolizumab and chemotherapy. Patients were randomized 1:1 to receive either 200 mg of pembrolizumab every 3 weeks for ≤35 cycles or investigator’s choice of chemotherapy regimens for ≤6 cycles. OS was the primary endpoint.

After a median follow-up of 12.8 months, 13.7% of patients were still on pembrolizumab and 4.9% were receiving the agent as maintenance therapy.

Response rates were higher among patients who received pembrolizumab: TPS ≥50% (39.5% vs. 32%), TPS ≥20% (33.4% vs 28.9%), and TPS ≥1% (27.3% vs 26.5%) compared with chemotherapy. Similarly, pembrolizumab showed superior duration of response in all three groups: TPS ≥50% (20.2 vs 10.8 months), TPS ≥20% (20.2 vs 8.3 months), and TPS ≥1% (20.2 vs 8.3 months).

In addition, these patients experienced fewer severe adverse events (AEs; 17.8% vs. 41%). Treatment-related AEs occurred more often in those who received chemotherapy (89.9% vs 62.7%) compared with pembrolizumabwhich led to discontinuation in 9.4% and 9% of patients, respectively.

“Lung cancer is a very dreadful disease. Every year, more than 230,000 patients develop it and 150,000 die from this disease,” said Lopes. “That is the equivalent of the whole population of Kansas City, Kansas, dying every year. It is a huge healthcare problem that we have just started to improve over the last 2 years.”

ASCO Expert John Heymach, MD, PhD, commended the study findings, saying that they represent an important milestone for patients with NSCLC.

“In an era for which chemotherapy was the only option for non—small cell lung cancer patients, this is coming to a close. Virtually all non–small cell lung cancer patients can receive a nonchemotherapy regimen with immunotherapy or, if they have a driver mutation, with an appropriate targeted agent,” Heymach said. “Immunotherapy is here to stay for the vast majority of non-small cell lung cancer patients as a firstline treatment. This represents a really important advance for these patients.”

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. Presented at: 2018 ASCO Annual Meeting; June 1-5; Chicago. Abstract LBA4.

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