Pembrolizumab improves outcomes in early-stage resectable lung cancer
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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 in The 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,” researcher Heather 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.
Researchers randomly assigned 397 patients to four cycles 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 demonstrated a safety 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.”
Perspective
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This study is not the only one to examine this approach. The AEGEAN trial showed an EFS benefit with neoadjuvant immunotherapy-chemotherapy, followed by adjuvant immunotherapy.
So, from a research standpoint, KEYNOTE-671 can be viewed as confirmatory study — and I feel good about the fact it is confirming what we saw before.
However, there are questions. Do those who achieved major pathologic response need adjuvant immunotherapy? And for those who did not achieve major pathologic response, is that a sufficient prognostic indicator for adjuvant immunotherapy? The jury is still out, but I remain optimistic that eventually we will become better at refining our patient populations.
I’m still a little confused about what this will do for clinicians. We already had an approval of a neoadjuvant immunotherapy from the CheckMate-816 trial, which assessed nivolumab (Opdivo, Bristol Myers Squibb) with chemotherapy in the neoadjuvant setting followed by surgery. Then we have the ADAURA trial, which led to approval of osimertinib (Tagrisso, AstraZeneca) as adjuvant therapy for patients with early-stage EGFR-mutated NSCLC. The IMpower010 study assessed adjuvant atezolizumab (Tecentriq, Genentech) plus chemotherapy in the adjuvant setting. So we have approvals in this space, and possibly another one coming based on AEGEAN.
So from a practice standpoint, how are clinicians going to prognosticate? That is not clear to me. The science is great, but it’s fragmenting clinical practice. I wouldn’t use the word ‘concern’, but it does give me a little bit of pause.
The other component is the importance of shared decision-making for patients with early-stage disease. We have different regimens available, but we still don’t know which is best. The CheckMate-816 regimen means after surgery, you’re done and not coming back. The Impower-010 regimen means you have surgery, and then you receive adjuvant treatment. The KEYNOTE-671 and AEGEAN regimens include neoadjuvant and adjuvant therapy. Those three paradigms require different considerations for our patients, so shared decision-making will be incredibly critical.
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Wakelee H, et al. Abstract LBA100. Presented at: ASCO Annual Meeting; June 2-6, 2023; Chicago.
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