KEYNOTE-042 Data Suggest Survival Improvement With Pembrolizumab in NSCLC

According to findings from the phase III KEYNOTE-042 trial, patients with non–small cell lung cancer demonstrated improved survival of 4 to 8 extra months with upfront pembrolizumab therapy compared with chemotherapy, the current standard of care. Patients treated with pembrolizumab also experienced fewer adverse events.

Gilberto Lopes, MD

According to findings from the phase III KEYNOTE-042 trial, patients with non—small cell lung cancer (NSCLC) demonstrated improved survival of 4 to 8 extra months with upfront pembrolizumab (Keytruda) therapy compared with chemotherapy, the current standard of care. Patients treated with pembrolizumab also experienced fewer adverse events (AEs; 17.8% vs. 41%). These results were presented at the 2018 ASCO Annual Meeting.

“Lung cancer is a very dreadful disease. Every year, more than 230,000 patients develop it and 150,000 die from this disease,” said lead study author Gilberto Lopes, MD, MBA, a medical oncologist at the Sylvester Comprehensive Cancer Center, University of Miami Health System in Florida. “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.”

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 (PFS) and overall survival (OS) compared with chemotherapy as a first-line treatment for metastatic NSCLC, in patients without targetable alterations with a PD-L1 tumor proportion score (TPS) of ≥50%.

“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.

The researchers separated patients into 3 arms according to TPS: ≥50% (n = 599), ≥20% (n = 818), and ≥% (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.

Pembrolizumab demonstrated superior OS, regardless of PD-L1 expression. OS was 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) compared with chemotherapy.

Response rates were also 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).

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.

“Pembrolizumab becomes an option for patients who have advanced non-small cell lung cancer and do not haveEGFRorALKmutations, and who do express PD-L1 at at least the 1% level,” said Lopes. “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.”

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.J Clin Oncol.2018;36(suppl; abstr LBA4).