More Positive Survival Data in Lung Cancer With Perioperative Therapy

SAN DIEGO — Patients with operable non-small cell lung cancer (NSCLC) had significantly longer event-free survival (EFS) with perioperative chemoimmunotherapy, a large randomized trial from China showed.

After a median follow-up of 2 years, treatment with the PD-L1 inhibitor adebrelimab and chemotherapy was associated with a 48% reduction in the EFS hazard as compared with chemotherapy plus placebo. The 2-year investigator-assessed EFS rate was 77.2% with adebrelimab and 58.5% with placebo, representing a 51% reduction in the EFS hazard. A preliminary analysis of overall survival (OS) yielded a 43% reduction in the OS hazard with the combination, and landmark analyses suggested a growing difference in favor of the adebrelimab arm.

The two treatment arms had almost identical rates of grade ≥3 treatment-related adverse events (TRAEs). Immune-mediated adverse events (imAEs) occurred more often with the PD-L1 inhibitor, but fewer than 5% of patients had grade ≥3 imAEs, reported Yi-Long Wu, MD, of Southern Medical University in Guangzhou, at the American Association for Cancer Research annual meeting.

“Definitive surgery and pCR [pathologic complete response] rates were also improved with adebrelimab and chemotherapy,” said Wu. “The benefits of pathological and clinical outcomes were consistent across subgroups. The circulating tumor [ct]DNA dynamics were predictive of pathological and clinical outcomes, providing a potential tool for refined perioperative risk stratification. Our findings support perioperative adebrelimab plus chemotherapy as a new treatment option for resectable stage II-III NSCLC.”

Potential for Tailored Therapy

Wu spoke during a session on advancing neoadjuvant and perioperative therapy. Session co-moderator Kenneth Tanabe, MD, of Mass General Brigham in Boston, observed how multiple presentations showed how ctDNA clearance or persistence can inform treatment decisions to tailor therapy.

Commenting on Wu’s study, Tanabe said, “It’s notable that on [the first day of cycle one], with respect to ctDNA, there is no improvement [in outcomes] with the immunotherapy. Is cycle one/day one ctDNA perhaps an opportunity to avoid the postoperative therapy?”

Wu pointed out that ctDNA levels continued to decrease during neoadjuvant therapy, such that only about 10% of patients remained ctDNA positive at the end of treatment. Additional patients became ctDNA negative following surgery.

“I think you will want to [continue therapy] in this setting,” said Wu. “These two points or landmarks are very important and predicted our outcomes.”

Co-moderator Alice Ho, MD, of Houston Methodist Academic Institute, said the study in NSCLC “mirrors what we saw in breast cancer, where after cycle one, about 50% of patients are positive, but then at the end of neoadjuvant therapy, you’re looking at a small number of patients who remain positive.”

In a summary at the end of the session, Tanabe highlighted use of the word “cure” in the session title (“Aiming for Cure: Perioperative Clinical Trials”).

“We don’t throw that term around loosely,” he said. “It’s a pretty bold term, but the point is that there are markers that identify patients with highest probability of long-term remission, so they provide a road map for strategic de-escalation that allows us to escalate for persistent molecular disease and safely explore an exit ramp for those patients whose biology has already achieved a complete reset and probably don’t need, for example, [16 cycles] of adjuvant immunotherapy out back.”

Study Background, Key Findings

The study added to a growing body of evidence that neoadjuvant and perioperative therapy can improve outcomes in operable NSCLC.

The randomized CheckMate 77T trial showed that adding nivolumab (Opdivo) to neoadjuvant chemotherapy reduced the EFS hazard by 42% and led to a 20% absolute improvement in EFS at 18 months. The multi-platform NeoCOAST trial showed improved pCR and major partial response (MPR) rates with various pairings of the PD-L1 inhibitor durvalumab (Imfinzi) with novel agents. The NeoTORCH trial from China showed a 60% reduction in the EFS hazard with the addition of the PD-1 inhibitor toripalimab to neoadjuvant chemotherapy.

The randomized trial that Wu reported included 501 patients with resectable stage II/III NSCLC with no prior systemic anticancer therapy and no targetable EGFR mutations or ALK rearrangements. Patients were randomized to receive three cycles of neoadjuvant chemotherapy plus adebrelimab or placebo, followed by surgery, followed by 16 cycles of adjuvant adebrelimab or placebo. The primary endpoints were EFS and MPR, both by independent review.

The study population had a median age of 60-61, men accounted for more than 90% of the patients, and more than 80% of the patients were current or former smokers. About 37% of patients had clinical stage II disease, about 47% had stage IIIA disease, and the rest had IIIB disease.

At the prespecified interim analysis, the adebrelimab arm had an event rate of 24.7% as compared with 38.4% for the placebo group (HR 0.52, 95% CI 0.38-0.72, P<0.0001). Patients allocated to the PD-L1 inhibitor had an MPR rate of 53.8% as compared with 18.4% for the placebo group (P<0.001), and pCR rates were 31.1% with adebrelimab and 7.6% with placebo. Subgroup analyses showed consistent EFS and MPR benefits favoring adebrelimab.

Thirty-two patients in the adebrelimab arm had died, compared with 50 in the placebo arm. Landmark OS analyses favored adebrelimab at 12 and 24 months (96.8% vs 91.9% and 89.1% vs 80.6%, respectively).

Grade ≥3 TRAEs occurred in about 53% of the patients, and TRAE-associated discontinuation rates were 8.0% and 4.4% for the adebrelimab and placebo groups. Rates of imAEs were 18.3% with adebrelimab and 9.2% with placebo, leading to discontinuation in 5.2% and 0.8% of patients, respectively.

The most common TRAEs in both groups were decreased neutrophil count, decreased white blood cell count, and anemia. The most common non-hematologic toxicities were increased liver enzymes, alopecia, nausea, and decreased appetite, also occurring in a similar proportion of patients in the two groups.

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