New Data in NSCLC Bolster Support for Perioperative Immunotherapy

— EFS motivate with pembrolizumab in KEYNOTE-671, however no OS motivate “yet,” says investigator

by
Ian Ingram, Managing Editor, MedPage As of late
June 5, 2023

CHICAGO — A randomized trial testing the addition of perioperative pembrolizumab (Keytruda) to chemotherapy in operable non-tiny cell lung most cancers (NSCLC) hit one in every of its two fundamental endpoints in an intervening time analysis, with a truly top trend for the a form of.

All sufferers in the watch got cisplatin-basically based entirely neoadjuvant chemotherapy, and at 2 years, the match-free survival (EFS) price reached 62.4% in those given pembrolizumab forward of and after surgery, in contrast with 40.6% for those assigned to placebo, reported Heather Wakelee, MD, of Stanford Most cancers Institute in California.

That distinction amounted to a 42% reduction in the probability for disease recurrence or loss of life (HR 0.58, 95% CI 0.46-0.72, P<0.001), and this EFS motivate in KEYNOTE-671 turn out to be fixed across all subgroups, including histology and PD-L1 standing, she detailed on the American Society of Scientific Oncology (ASCO) assembly here.

But on total survival (OS), “now we haven’t yet crossed the significance boundary,” acknowledged Wakelee. “On the opposite hand, at the present we construct peek the curves starting to separate.”

At 2 years, an estimated 80.9% of sufferers were alive in the pembrolizumab arm versus 77.6% in the placebo arm (HR 0.73, 95% CI 0.54-0.ninety nine), in accordance with findings from the watch, which were published simultaneously in the New England Journal of Treatment.

Despite that, Wakelee concluded that the records improve the perioperative exercise of the PD-1 checkpoint inhibitor in resectable stage II-III NSCLC, and the findings extra toughen the role of checkpoint blockade in operable sufferers.

Pembrolizumab is already accredited by the FDA in the adjuvant environment, as is atezolizumab (Tecentriq). And last yr, the agency accredited neoadjuvant nivolumab (Opdivo) in resectable NSCLC in accordance with the CheckMate-816 trial.

Within the last few months, two a form of perioperative trials testing PD-1/L1 inhibitors in early NSCLC — particularly investigational toripalimab and durvalumab (Imfinzi) — confirmed motivate in the Neotorch and AEGEAN trials.

These perioperative immunotherapy compare, including KEYNOTE-671, list “a fundamental advance as recent standards of enjoyment in the therapy of resectable lung most cancers,” acknowledged ASCO-invited discussant Designate Awad, MD, PhD, of the Dana-Farber Most cancers Institute in Boston.

But “may perchance presumably fair composed we give it pre-op, post-op, or every?” he requested.

Even supposing Awad cautioned that the records are immature, “there appears to be like to be an encouraging designate for total survival motivate favoring a neoadjuvant plus or minus adjuvant immunotherapy manner.” He identified that intervening time analyses from adjuvant-easiest section III trials — IMpower010 and KEYNOTE-091/PEARLS — possess yet to prove a transparent separation in OS curves.

On the additive role of adjuvant immunotherapy when sufferers possess already got neoadjuvant chemoimmunotherapy, Awad advised that extra watch is compulsory. “For now, I deem it be reasonable to continue adjuvant immunotherapy in dialogue with our sufferers,” he acknowledged.

The double-blind KEYNOTE-671 trial enrolled NSCLC sufferers with stage II-IIIB (N2) disease deemed match for surgery. Total, 797 participants were randomized 1:1 to either the perioperative pembrolizumab plan or to the modify arm.

All sufferers got four cycles of neoadjuvant chemotherapy (cisplatin plus either gemcitabine or pemetrexed [Alimta] reckoning on histology) with IV pembrolizumab (200 mg) or placebo every 3 weeks. Following surgery, sufferers in the 2 arms got up to 13 cycles of adjuvant pembrolizumab on the the same dose and schedule, or placebo.

Stratification factors incorporated disease stage, PD-L1 expression, histology, and geographic enviornment.

Patients in the watch had a median age of 63-64, and over 70% were men. Most were white (60%), and 31% were Asian. A majority of the participants had a smoking history.

For disease traits, 57% had nonsquamous histology, and 70% had pathologic stage III disease at baseline. About a third had ≥50% PD-L1 expression, a third had 1-49% PD-L1 expression, and a third had <1% PD-L1 expression.

Three-fourths of sufferers carried out all four cycles of neoadjuvant therapy, with about 85% going on to surgery. Within the adjuvant environment, 73% of sufferers in the pembrolizumab arm got now not lower than one dose versus 67% of those in the modify community (40% and 35% carried out all 13 planned cycles).

EFS and OS in the intent-to-cope with inhabitants constituted the dual fundamental endpoints, with secondary endpoints including fundamental pathological response (MPR), pathologic total response (pCR), and safety.

Following surgery, rates of MPR and pCR every vastly most traditional the investigational arm versus the modify arm (P<0.0001 for every):

• MPR: 30.2% vs 11%, respectively
• pCR: 18.1% vs 4.0%

Toxicity turn out to be “as anticipated,” acknowledged Wakelee, and reflective of a patient inhabitants who had chemotherapy and went on to surgery.

Grade ≥3 therapy-linked detrimental occasions (AEs) were extra frequent in the pembrolizumab arm (forty five% vs 37%) and a elevated percentage of sufferers in that arm discontinued all therapy which skill of AEs (13% vs 5%). There were four and three therapy-linked deaths, respectively.

As anticipated, immune-mediated AEs were elevated with the checkpoint inhibitor, with grade ≥3 immune-mediated AEs in 5.8% versus 1.3% of the modify arm.