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The current standard of care for patients with metastatic non-small cell lung cancer (NSCLC) and a PD-L1 tumor proportion score (TPS) from 1% to 49% is chemotherapy plus pembrolizumab (Keytruda). However, the of pembrolizumab's label to include single-agent treatment for these patients with a lower TPS has called into question the appropriate first-line management of these patients.

Pembrolizumab monotherapy was previously approved in patients with metastatic disease and PD-L1 expression of 50% or greater. Patients with a lower TPS, generally received chemotherapy plus pembrolizumab, according to Anne Tsao, MD, of MD Anderson Cancer Center in Houston.

"I don't see that changing in medically fit patients," Tsao told MedPage Today. "But, this is a very controversial area that is currently being debated in the field."

KEYNOTE-042

The expansion of pembrolizumab's label was based on the KEYNOTE-042 phase III trial. Results presented at the 2018 ASCO Annual Meeting indicated that in patients with advanced NSCLC treatment with pembrolizumab resulted in a greater median survival than standard chemotherapy, even in patients with low levels of PD-L1.

Among 599 patients with PD-L1 expression of 50% or greater, median overall survival was 20 months with pembrolizumab compared with 12.2 months for chemotherapy (HR 0.69, P=0.003). Among 818 patients with PD-L1 expression of 20% or greater, the median overall survival was 17.7 months compared with 13 months, respectively (P=0.002). Finally, among the total population of 1,237 patients, all of whom had a PD-L1 expression of 1% or greater, median overall survival was 16.7 months compared with 12.1 months (P=0.0018).

"When we saw final data though, it was quite clear that patients at the 1% to 49% level didn't benefit that much," said Roy S. Herbst, MD, PhD, of Yale Cancer Center and Smilow Cancer Hospital in New Haven, Connecticut. "Most of the benefit was in patients at 50% or greater."

The final KEYNOTE-042 results, published recently in by Tony Mok, MD, of Chinese University of Hong Kong, and colleagues, included an exploratory analysis of only those patients with PD-L1 TPS of 1% to 49% that showed no significant overall survival difference between the two arms (HR 0.92, 95% CI 0.77-1.11).

Tsao pointed out that close to one-half of the patients enrolled in the study had a PD-L1 TPS of 50% of greater -- higher than what is typically seen -- 20% to 30%.

"These were the patients that were driving the positive result of the trial," Tsao said.

FDA Decision

Despite the result of this exploratory analysis, neither Herbst nor Tsao said that they entirely disagree with the FDA's decision to expand single-agent pembrolizumab's label.

"The trial was written with a 1% threshold and it was positive at the 1% threshold," Herbst said. "It won approval on that design."

However, he noted that as part of the shared-decision making process, clinicians and patients should discuss the ins and outs of this treatment regimen and figure out the best approach together.

Similarly, Tsao said that in her clinical practice she would likely not give single-agent pembrolizumab in patients with a PD-L1 TPS of 1% to 49% with good performance status who can tolerate chemotherapy plus immunotherapy.

Chemotherapy is not an option for every patient though, Tsao noted. For example, some patients are frail and very old and do not have adequate organ function to undergo chemotherapy.

"Immunotherapy is easier to give in that sense, but there are also several contraindications for immunotherapy as well," Tsao said.

In addition, given that PD-L1 is a heterogeneous biomarker that can vary based on the tissue biopsied, Tsao said that she understands why the FDA expanded the label.

"What the FDA's approval allows us to do is, in patients who were unable to get enough tumor tissue to test for PD-L1 or in those who have low PD-L1 score but are unable to get chemotherapy for any reason, this allows us to give them treatment," Tsao said. "Before this decision, these patients might have gone to hospice."

Definitive Answer

In their discussion of the KEYNOTE-042 results, Mok and colleagues mentioned results from (carboplatin-pemetrexed-pembrolizumab in nonsquamous NSCLC) and KEYNOTE-407 (carboplatin-taxane-pembrolizumab in squamous NSCLC) trials, which showed improved overall and progression-free survival when pembrolizumab was given in combination with platinum-doublet chemotherapy, regardless of PD-L1 TPS.

"Although pembrolizumab plus chemotherapy might have greater efficacy than pembrolizumab alone in patients with PD-L1-expressing tumors, particularly those with lower PD-L1 expression levels, a definitive conclusion cannot be made without a prospective direct comparison," Mok and colleagues wrote.

Herbst is currently involved in a trial doing just that. is testing first-line immunotherapy with pembrolizumab alone or in combination with chemotherapy as induction/maintenance or as post-progression therapy in patients with advanced NSCLC.

Herbst said the hope is that this trial will help to address sequencing of therapies by directly comparing single-agent pembrolizumab in PD-L1 positive patients to a three-drug combination. The trial will include a biomarker evaluation component and will compare outcomes by treatment arm within subgroups defined by the PD-L1 expression cutpoint of 50% or greater.

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