Akeso’s VEGF/PD-1 Boosts Lung Cancer Survival, Relieving Pressure on US Partner Summit

Akeso's Ivonescimab Achieves Significant Overall Survival Benefit in Squamous NSCLC

Akeso's HARMONi-6 Phase 3 trial, conducted in China, demonstrated a significant overall survival (OS) benefit for its VEGF/PD-1 bispecific therapy, ivonescimab, combined with chemotherapy. The study involved 532 patients with first-line advanced squamous non-small cell lung cancer (NSCLC). Treatment with ivonescimab plus chemotherapy resulted in an OS of 27.9 months, compared to 23.7 months for the control arm (BeOne’s Tevimbra plus chemotherapy). This outcome was statistically significant, with a hazard ratio (HR) of 0.66, exceeding expert expectations and being hailed as clinically meaningful and potentially practice-changing.

• The HARMONi-6 Phase 3 trial, run by Akeso in China, achieved a statistically significant overall survival (OS) benefit for ivonescimab plus chemotherapy in 532 patients with first-line advanced squamous non-small cell lung cancer (NSCLC). The treatment arm showed an OS of 27.9 months, a 4.2-month improvement over the 23.7 months in the control arm (BeOne’s Tevimbra plus chemotherapy). The hazard ratio (HR) was 0.66, a result that was considered clinically meaningful and practice-changing by experts, significantly surpassing their anticipated benchmarks.
• This OS update was highly anticipated, especially after previous HARMONi-6 data had shown promising progression-free survival (PFS) but immature OS results. Analysts and key opinion leaders had set high expectations, with some suggesting an HR of 0.70-0.72 would be good, and 0.75 or lower a 'complete game changer.' The achieved HR of 0.66 not only cleared these bars but also defied typical expectations for VEGF agents, which usually do not reach such low hazard ratios, underscoring the potential of this bispecific therapy.
• The positive HARMONi-6 data is critical for Akeso and its US partner Summit Therapeutics, particularly as they work to replicate these findings in a global population through the HARMONi-3 trial. While an early interim analysis of HARMONi-3's PFS was disappointing, the strong OS from HARMONi-6 provides crucial momentum. Summit has also submitted ivonescimab to the FDA for locally advanced or metastatic non-squamous NSCLC with EGFR mutations, with a decision expected in November, positioning it as a potential competitor to Merck’s Keytruda.

Ivonescimab's HARMONi-6 Delivers Clinically Meaningful OS Benefit

A recent network meta-analysis of 24 randomized controlled trials involving 5,035 patients with PD-L1-negative advanced NSCLC demonstrated that anti-PD-1 plus chemotherapy significantly improved both progression-free survival (HR = 0.58, 95% CI: 0.50-0.68) and overall survival (HR = 0.71, 95% CI: 0.57-0.88) compared to chemotherapy alone in squamous NSCLC patients. Notably, anti-PD-L1 plus chemotherapy combinations showed no significant benefit in this histological subtype (PFS: HR = 0.81; OS: HR = 0.87; P > 0.05), highlighting the importance of histology-driven treatment strategies. The Phase III AK105-302 trial evaluated penpulimab, a novel PD-1 inhibitor, combined with carboplatin-paclitaxel in metastatic squamous NSCLC, demonstrating significant improvements in both progression-free survival and overall survival with a favorable safety profile compared to placebo plus chemotherapy.

Real-world evidence from a retrospective study of 433 squamous NSCLC patients receiving first-line pembrolizumab plus carboplatin/(nab)-paclitaxel showed a median overall survival of 12.9 months (95% CI: 10.3-17.1) with a 5-year overall survival rate of 18.2%. The 5-year survival rates varied significantly by PD-L1 expression levels, with patients having ≥50% PD-L1 expression achieving 32.6% survival compared to 15.2% and 14.1% for those with <1% and 1-49% expression, respectively. A separate analysis comparing taxane-based versus gemcitabine-based platinum doublets in stage IV squamous NSCLC demonstrated superior outcomes for taxane combinations, with significantly improved overall survival (HR: 0.638, 95% CI: 0.497-0.821, p = 0.0004) and progression-free survival (HR: 0.686, 95% CI: 0.532-0.885, p = 0.0035), while maintaining comparable adverse event profiles.

For the subset of patients with ALK-rearranged squamous NSCLC, a retrospective study of 28 patients with stage IIIC-IV disease showed that first-line ALK-TKI treatment significantly improved outcomes compared to chemotherapy, with median progression-free survival extending from 3.0 to 16.0 months (P < 0.01) and overall survival from 18.5 to 30.0 months (P = 0.039). Objective response rates were substantially higher with ALK-TKIs at 75% versus 25% with chemotherapy (P = 0.021). Patient-derived xenograft studies validated the efficacy of various ALK-TKIs including crizotinib, alectinib, and lorlatinib, with one patient harboring a novel CSNK1G3-ALK fusion achieving durable disease control with first-line alectinib for over 30 months.

Designing HARMONi-6: A Landmark Trial in Squamous NSCLC

Recent landmark trials in advanced squamous NSCLC have established critical benchmarks for treatment efficacy and safety across diverse therapeutic approaches. These studies span from novel targeted therapies to immunotherapy combinations, providing comprehensive insights into optimal treatment paradigms for this challenging malignancy.

Ivonescimab's Unique Bispecific Approach in the NSCLC Pipeline

Ivonescimab represents a unique bispecific approach targeting both PD-1 and VEGF pathways simultaneously in NSCLC treatment. The available literature does not identify other drugs currently in clinical trials that employ the same dual PD-1/VEGF bispecific mechanism as ivonescimab. While several other bispecific antibodies are under development for solid tumors, they target different pathway combinations and remain primarily in early-phase studies.

Ivonescimab's OS Breakthrough: Reshaping Squamous NSCLC Care

The recent announcement regarding Akeso's HARMONi-6 Phase 3 trial marks a pivotal moment for patients battling first-line advanced squamous non-small cell lung cancer (NSCLC). This patient population has historically faced limited therapeutic options and poorer prognoses compared to other NSCLC subtypes. The demonstration of a statistically significant and clinically meaningful overall survival (OS) benefit with ivonescimab, a novel VEGF/PD-1 bispecific antibody, combined with chemotherapy, offers a beacon of hope. Achieving a median OS of 27.9 months, a substantial improvement over the control arm's 23.7 months, positions this regimen as a strong contender for a new standard of care.

This outcome builds upon earlier data showing a significant progression-free survival (PFS) advantage, consistent across all PD-L1 expression levels, which is particularly important for broader applicability. The dual targeting mechanism of ivonescimab, simultaneously inhibiting VEGF and PD-1 pathways, appears to confer a synergistic effect that translates into superior patient outcomes.

However, as with any potent therapy, careful consideration of the risk-benefit profile is essential. Studies indicate a higher rate of grade 3 or higher treatment-related adverse events, including haemorrhage, in the ivonescimab arm. This underscores the importance of vigilant patient monitoring and proactive management of potential side effects. Furthermore, while the data is robust, the trial's execution solely within China suggests that further validation in diverse global populations may be beneficial to fully understand its broader applicability and efficacy across different genetic backgrounds and healthcare settings. The long-term safety and durability of the maintenance phase, extending up to 24 months, will also be critical as more mature data becomes available. Despite these considerations, the compelling OS data represents a significant leap forward, offering a new, highly effective treatment strategy for a challenging cancer.