Ivonescimab's Strong China NSCLC Data Faces a Hard FDA Precedent; HARMONi-3 Is the Deciding Factor

Summit and Akeso Address China-First Trial Challenges for Ivonescimab

The article highlights the growing trend of China-first clinical trials for novel cancer therapies and the regulatory challenges faced by transnational partnerships, exemplified by Summit Therapeutics and Akeso's ivonescimab. Despite strong efficacy data from China-based Phase 3 trials, including a 49% reduction in disease progression or death and a 34% reduction in death risk for ivonescimab in NSCLC, U.S. regulators often require evidence of efficacy translation to Western populations. The FDA's past rejection of Eli Lilly's sintilimab, based solely on China data, underscores the need for multi-regional trials or bridging studies. Summit and Akeso are currently awaiting data from their multiregional HARMONi-3 trial to address these concerns and secure potential FDA approval.

• Summit Therapeutics and Akeso's PD-1/VEGF-targeting antibody, ivonescimab, demonstrated significant efficacy in the China-based Phase 3 HARMONi-6 study for non-small cell lung cancer (NSCLC). Data showed a 49% reduction in the risk of disease progression or death and a 34% reduction in the risk of death in Chinese patients, outperforming Merck's Keytruda.
• The FDA has shown reluctance to approve drugs based solely on single-country data, particularly from China, due to potential differences in patient populations, disease drivers, and post-trial care. This stance was reinforced by the rejection of Eli Lilly's sintilimab, which lacked a multiregional trial, emphasizing the need for sponsors to demonstrate efficacy translation to U.S. or global populations.
• To secure Western approvals, companies are advised to expand trial regions early or, for completed single-region trials, engage with the FDA for options like robust post-marketing requirements or bridging studies. Summit and Akeso are conducting the multiregional HARMONi-3 trial, which includes North American and European patients, with initial data expected in the second half of this year and an FDA decision anticipated by November 14.

The Evolving NSCLC Landscape: China-First Trials and Western Approval

The treatment landscape for non-small cell lung cancer (NSCLC) has been revolutionized by immunotherapy, establishing a new standard of care. Landmark trials such as KEYNOTE-189 and CheckMate 227 have proven the long-term overall survival benefits of first-line immunotherapy combinations, including pembrolizumab plus chemotherapy or nivolumab plus ipilimumab, irrespective of PD-L1 expression status. Further strategies, like the limited-course chemotherapy plus immunotherapy doublet evaluated in the CheckMate 9LA study, aim to provide rapid disease control while minimizing chemotoxicity. The pipeline continues to evolve with novel targets, evidenced by the phase II CITYSCAPE trial, which showed significant response rates with the TIGIT inhibitor tiragolumab combined with atezolizumab in PD-L1 positive NSCLC. For patients who progress on initial therapies, rechallenge strategies combining a PD-1 inhibitor with either chemotherapy or anlotinib have also demonstrated measurable antitumor activity and encouraging survival outcomes.

Concurrently, advances in targeted therapy have transformed outcomes for patients with specific oncogenic drivers. For ALK-positive NSCLC, the phase III CROWN trial established the superiority of the third-generation TKI lorlatinib over crizotinib in treatment-naïve patients, showing enhanced systemic and intracranial efficacy. The field has similarly advanced for EGFR-mutated NSCLC, with the ADAURA trial proving that adjuvant osimertinib significantly prolongs disease-free survival. More recently, trials like FLAURA2 and MARIPOSA have shown that intensifying first-line treatment with osimertinib plus chemotherapy or amivantamab-lazertinib prolongs survival compared to osimertinib monotherapy, particularly in high-risk subgroups. The scope of targeted agents has also broadened to include other drivers, with drugs like trastuzumab deruxtecan showing high efficacy for HER2-mutated patients and pralsetinib being approved for RET fusion-positive NSCLC.

Emerging trends point toward increasingly sophisticated combination strategies and novel therapeutic modalities designed to overcome resistance. For patients without common driver mutations, the combination of the anti-angiogenic TKI anlotinib with an immune checkpoint inhibitor like sintilimab has demonstrated superior progression-free survival and overall response rates compared to chemotherapy in the first-line setting. Furthermore, antibody-drug conjugates (ADCs) are emerging as a promising class of therapeutics, with initial reports showing activity against genomic alterations and central nervous system metastases. The development of multi-target TKIs like anlotinib, which has shown activity in KRAS-mutant lung cancer, and the exploration of macrophage-targeting therapies reflect a multi-pronged approach to a complex disease, with a focus on improving outcomes across diverse patient populations.

Designing Global NSCLC Trials: Addressing Population Heterogeneity for FDA

Pivotal NSCLC trials define eligibility through a combination of histological confirmation, biomarker status, disease stage, prior treatment exposure, and performance status — criteria that directly shape how generalizable results are across global, real-world populations. As sponsors design trials for FDA submission, addressing historical exclusion patterns (particularly around brain metastases and poor performance status) is increasingly critical to reflect population heterogeneity and support broader regulatory and clinical applicability.

• Disease stage and histology confirmation: Trials such as TROPION-Lung14 require histologically/cytologically confirmed stage IIIB/IIIC or IV non-squamous NSCLC, with biomarker-defined subgroups (e.g., EGFR Ex19del or L858R mutations) forming the core inclusion criteria.

• Prior treatment history: Most pivotal trials mandate treatment-naïve status for advanced disease (no prior EGFR-TKI or systemic therapy), as seen in TROPION-Lung14; however, real-world data show gaps in this pathway — 19% of biomarker-positive patients at Princess Margaret Cancer Centre started chemotherapy before results were available, highlighting turnaround-time challenges in trial feasibility.

• Biomarker testing and selection: Molecular stratification (EGFR, ALK, PD-L1) is central to eligibility, but testing rates and turnaround vary — only 72% of nonsquamous NSCLC patients in one cohort underwent biomarker testing, and just 21% had results at initial consultation. Biomarker-positive patients skew toward female, Asian, and never-smoker demographics, raising representativeness concerns for global trial design.

• Performance status stratification: Trials commonly stratify by WHO/ECOG performance status (e.g., 0 vs. 1 in TROPION-Lung14), yet poor-PS patients are underrepresented despite real-world evidence that non-elective referrals (19% of NSCLC patients) are strongly associated with worse PS (OR 7.28 for PS 4), and case data showing meaningful clinical improvement with immunotherapy even in PS 3 patients.

• Brain metastases eligibility: Historically, over 80% of NSCLC trials excluded patients with brain metastases, and current protocols requiring completed radiotherapy with prolonged washout periods further limit inclusion — only 11.4% of lung cancer trials permit active, untreated BM despite ASCO-Friends of Cancer Research and FDA guidance encouraging broader inclusion.

• Recommended BM inclusion framework (2026): Emerging guidance supports enrolling patients with GPA-predicted survival ≥12 months (or EQ ≥0.50), permitting asymptomatic untreated BM with protocol-defined CNS imaging intervals (4–6 weeks), stratifying by GPA category, and prospectively applying RANO-BM or modified RECIST criteria — with separate reporting of full analysis sets versus evaluable CNS disease subsets.

• Multimodality and surgical trial feasibility: In trials involving resectable disease (e.g., PIONEER, stage III-N2 NSCLC), stringent eligibility narrows the enrollable population substantially (only 19% of screened patients were eligible), and completion of planned multimodality treatment remains a challenge (50–65% completion rates), underscoring the real-world attrition between eligibility and full protocol adherence.