Pembrolizumab improves outcomes in early-stage resectable lung cancer

Key takeaways:

• Pembrolizumab in the neoadjuvant and adjuvant settings extended EFS vs. chemotherapy alone.
• Researchers reported higher major pathologic response and pathologic complete response rate with pembrolizumab.

CHICAGO — The addition of pembrolizumab to neoadjuvant chemotherapy followed by adjuvant pembrolizumab improved outcomes for patients with early-stage resectable non-small cell lung cancer, according to findings presented at ASCO Annual Meeting.

Results of the randomized phase 3 KEYNOTE-671 trial — published simultaneously inThe New England Journal of Medicine— showed a statistically significant improvement in EFS, as well as higher pathologic complete response and major pathologic response rates, among patients assigned pembrolizumab.

“We saw a 42% improvement in event-free survival, so it’s clear this is impacting a very high percentage of patients,” researcherHeather Wakelee, MD,professor of medicine (oncology) with Stanford Medicine, told Healio. “That profound impact on event-free survival is very likely to have an overall survival benefit. We can’t say that definitively because there haven’t been enough events to make that determination, but we are seeing separation of the curves and I’m very hopeful that we will see an overall survival benefit.”

Background

Single-agent pembrolizumab (Keytruda, Merck) — an anti-PD-1 antibody — has demonstrated effectiveness as adjuvant therapy for patients with NSCLC. It also has exhibited efficacy in combination with chemotherapy for patients with metastatic disease.

Wakelee and colleagues conducted the double-blind KEYNOTE-671 trial to determine whether the addition of pembrolizumab to neoadjuvant platinum-based chemotherapy, followed by resection and adjuvant therapy with pembrolizumab, would improve outcomes for patients with early-stage NSCLC.

“The field is evolving very rapidly in terms of how we care for patients with early-stage lung cancer,” Wakelee said. “We have had positive trials with either a pure adjuvant approach or a pure neoadjuvant approach but there was still room for improvement. With this trial, we wanted to combine both strategies.

“We hoped combining immune therapy with chemotherapy before surgery would give patients the most optimal surgical outcome and prime the immune response when there was still more tumor available to be recognized by the immune system,” Wakelee said.

Methods

The trial included 797 patients with stage II, IIIA or IIIB resectable NSCLC. All participants had ECOG performance status of 0 or 1.

人员397名患者随机分配到4cycles of 200 mg pembrolizumab plus cisplatin-based neoadjuvant chemotherapy, followed by surgery, followed by 13 cycles of adjuvant pembrolizumab. The other 400 patients received placebo plus neoadjuvant chemotherapy, followed by surgery, followed by placebo for an additional 13 cycles.

Stratification factors included PD-L1 tumor positive score (< 50% vs. 50%), disease stage (II vs. III), histology (squamous vs. nonsquamous) and region (east Asia vs. elsewhere).

EFS and OS in the intention-to-treat population served as dual primary endpoints.

Major pathologic response and pathologic complete response assessed by blinded independent pathology review, along with safety, served as secondary endpoints.

Researchers defined major pathologic response as 10% or less viable tumor cells in the resected primary tumor and lymph nodes. They defined pathologic complete response as ypT0/TisypN0.

Results

Median follow-up was 25.2 months (range, 7.5-50.6).

Results showed a significant EFS improvement with pembrolizumab vs. placebo (median, not reached vs. 17 months; HR = 0.58; 95% CI, 0.46-0.72). A higher percentage of patients assigned pembrolizumab achieved 2-year EFS (62.4% vs. 40.6%).

Researchers reported significantly higher major pathologic response rate (30.2% vs. 11%; difference, 19.2%; 95% CI, 13.9-24.7) and pathologic complete response (18.1% vs. 4%; difference, 14.2%; 95% CI, 10.1-18.7) in the pembrolizumab group.

“Outcomes like major pathologic response and pathologic complete response are our guide to how much benefit patients derived from those four cycles before surgery,” Wakelee told Healio. “Patients who had that really profound response were more likely to do well.”

However, patients who did not achieve such a strong response after neoadjuvant pembrolizumab ultimately exhibited favorable outcomes, Wakelee said.

“We can’t really tease out the long-term benefits still happening from the neoadjuvant approach vs. the additional benefits from the adjuvant approach, but we do see a clear benefit from pembrolizumab given in the adjuvant setting,” she said.

Only 177 events had occurred at data cutoff. Although OS results approached statistical significance, the boundary had not been crossed (HR = 0.73; 95% CI, 0.54-0.99).

“With prior trials that used an immune checkpoint inhibitor in the perioperative setting, the survival benefit continued to grow over time,” Wakelee said. “I think that speaks to the likelihood that we are truly changing outcomes for these patients. We don’t see that as much with other approaches that are not immune-based.”

The majority of patients in the pembrolizumab and placebo groups underwent definitive surgery (80.6% vs. 75.5%), and most patients in each group had R0 resection (92% vs. 84%).

Pembrolizumab演示了一个安全的ty profile consistent with prior reports. Researchers observed no new safety signals.

A numerically higher percentage of patients in the pembrolizumab group experienced grade 3 or higher treatment-related adverse events (44.9% vs. 37.3%), treatment-related adverse events that led to discontinuation of all therapy (12.6% vs. 5.3%), and treatment-related adverse events that led to death (1% vs. 0.8%).

More than twice as many patients assigned pembrolizumab developed any-grade immune-mediated adverse events (25.3% vs. 10.5%).

Next steps and implications

Investigators will conduct additional analyses for OS per the statistical plan.

The findings suggest the valuable role of immune therapy in the neoadjuvant setting when the probability of immune response is highest, Wakelee said.

“It does improve surgical outcomes,” she said. “There is a benefit for adjuvant treatment in the big picture, too. ... But when you have a patient who you know is going to need systemic therapy, getting that systemic therapy started sooner in a way that doesn’t interfere with the ability to do the definitive surgical treatment really is a win for the patient.”