Upfront Ivonescimab Plus Chemo Bests PD-1 Inhibitor Combo in Advanced NSCLC

CHICAGO — A first-in-class bispecific antibody targeting PD-1 and VEGF combined with chemotherapy significantly improved overall survival (OS) in patients with advanced squamous non-small cell lung cancer (NSCLC), according to the HARMONi-6 trial.

At a median follow-up of 21.4 months, the ivonescimab-chemotherapy combination in the first line reduced the risk of death by 34%, with a median OS of 27.9 months versus 23.7 months with tislelizumab (Tevimbra) plus chemotherapy (HR 0.66, 95% CI 0.50-0.87, P=0.0017), reported Shun Lu, MD, PhD, of the Shanghai Chest Hospital-Jiao Tong University School of Medicine, at a press briefing at the American Society of Clinical Oncology (ASCO) annual meeting. HARMONi-6 data also were published in The Lancet.

Estimated OS rates at 24 months were 64.7% in the ivonescimab group and 48.6% in the tislelizumab group, while the corresponding rates at 18 months were 70.5% and 61.3%, and at 12 months were 78.9% and 72.2%, respectively.

Lu and colleagues previously reported that HARMONi-6 met its primary outcome of progression-free survival (PFS), with ivonescimab-chemotherapy significantly improving median PFS by about 4 months versus tislelizumab-chemotherapy (11.1 months vs 6.9 months, HR 0.60, 95% CI 0.46–0.78, P<0.0001).

The results from HARMONi-6 “support the adoption of ivonescimab plus chemotherapy as a new standard of care for patients with advanced squamous non-small cell lung cancer as first-line treatment in China,” Lu said.

He added that the recruiting phase III HARMONi-3 study will evaluate ivonescimab-chemotherapy versus pembrolizumab (Keytruda) and chemotherapy for the first-line treatment of patients with squamous and non-squamous metastatic NSCLC.

ASCO discussant David R. Spigel, MD, of the Sarah Cannon Research Institute in Nashville, Tennessee, noted that HARMONi-6 is the first large prospective trial to show that an anti-PD-1/VEGF bispecific therapy plus chemotherapy is superior to the established standard of PD‑1 inhibitor plus chemotherapy in patients with advanced squamous lung cancer.

“The other point about this study that I think is noteworthy is it was trying to go after a group of patients…where there’s been a largely unmet medical need in squamous lung cancer,” he stated. “Although we’ve had advanced immunotherapy, this group still often has a very poor prognosis, even with advanced therapies like chemotherapy and immunotherapy.”

While PFS and OS endpoints were met, Spigel cautioned that the trial took place in China “so it’s hard to know how this applies to a population of patients beyond there. Were waiting on other studies, like the HARMONi-3 study, but these [current] results are certainly very encouraging.”

HARMONi-6 was conducted at 50 sites and included 532 patients with previously untreated, pathologically confirmed, unresectable stage IIIB, IIIC, or stage IV squamous NSCLC.

Patients were randomly assigned to receive IV ivonescimab or tislelizumab, plus IV paclitaxel and carboplatin once every 3 weeks for four cycles, followed by ivonescimab or tislelizumab (200 monotherapy as maintenance treatment for up to 24 months).

In both treatment groups, the vast majority of participants were male, current or former smokers, and had stage IV disease, while 39% in each group had a PD-L1 tumor proportion score (TPS) of less than 1%.

There was a consistent OS benefit with ivonescimab-chemotherapy across key subgroups, including patients with:

• PD-L1 TPS <1%: HR 0.64 (95% CI 0.43-0.96)
• PD-L1 TPS of ≥1%: HR 0.68 (95% CI 0.46-0.99)
• PD-L1 TPS 1-49%: HR 0.67 (95% CI 0.42-1.05)
• PD-L1 TPS ≥50%: HR 0.64 (95% CI 0.32-1.31)

Regarding safety, treatment-related adverse events (TRAEs) grade ≥3 occurred in 69% of patients in the ivonescimab group and 59% in the tislelizumab group. Rates of TRAEs leading to treatment discontinuation were the same in both groups (5%), as were the rates of TRAEs resulting in death (4%).

Immune-related AEs grade ≥3 were also similar in both groups (14%).