Summit Therapeutics' High-Stakes FDA BLA Gamble: Assessing the Binary Catalyst Risk and Reward

Summit Therapeutics is poised to make a bold regulatory move in the fourth quarter of 2025, submitting a Biologics License Application (BLA) for ivonescimab in combination with chemotherapy for second-line or greater treatment of EGFR-mutant non-small cell lung cancer (NSCLC). This filing hinges on the HARMONi Phase III trial, which demonstrated a 48% reduction in the risk of disease progression or death (progression-free survival, or PFS) compared to chemotherapy alone but failed to achieve statistical significance in overall survival (OS). The FDA has historically required OS improvements for marketing authorization in this setting according to regulatory guidelines, creating a binary catalyst for investors: approval based on PFS alone or rejection due to unmet OS benchmarks.

The HARMONi Trial: A Double-Edged Sword

The HARMONi study's PFS results are compelling. Ivonescimab plus chemotherapy reduced progression or death by 48%, with consistent benefits observed across both Asian and Western patient populations. Summit has emphasized that these findings, combined with the drug's favorable safety profile and the absence of FDA-approved therapies with proven OS benefits in this patient cohort, justify the BLA. However, the lack of OS improvement-a metric the FDA has explicitly tied to approval in similar cases-introduces significant regulatory uncertainty.

This tension mirrors broader debates in oncology drug development. While PFS is a clinically meaningful endpoint, it is often criticized as a surrogate marker that may not reliably predict long-term survival benefits. For instance, datopotamab deruxtecan (Dato-DXd), approved in 2025 for HR-positive, HER2-negative breast cancer, showed a 6.9-month PFS improvement over chemotherapy but no OS benefit. Such precedents suggest the FDA is willing to accept PFS-driven approvals in settings with high unmet need, but they also highlight the risk of post-approval scrutiny if OS data fail to materialize.

FDA Precedents: A Mixed Bag for Investors

Historical data reveals a nuanced regulatory landscape. Between 2006 and 2023, only 22% of oncology drug approvals were based on OS, while 33% relied on immature or surrogate endpoints like PFS according to clinical analysis. Of these, 74% later failed to demonstrate OS improvements in post-approval trials according to clinical analysis. This trend underscores a key risk for Summit: even if the BLA is accepted, the FDA may demand confirmatory trials or impose restrictive labeling, limiting commercial potential.

Conversely, the agency's recent flexibility in approving drugs for rare or refractory cancers-such as the 2025 approval of Dato-DXd-suggests a willingness to prioritize PFS in cases of unmet need. Summit's argument that ivonescimab addresses a "no-therapy" scenario could resonate with regulators, particularly if the company leverages real-world evidence or key opinion leader endorsements to bolster its case.

Risk vs. Reward: A Binary Proposition

For investors, the BLA submission represents a high-risk, high-reward binary event. If approved, ivonescimab could capture a significant share of the EGFR-mutant NSCLC market, a segment projected to grow as resistance to first-line EGFR tyrosine kinase inhibitors (TKIs) becomes more prevalent. Summit's confidence in the drug's safety profile and early physician feedback further strengthens the upside according to recent reports.

However, rejection would be catastrophic. The company has limited financial resources to fund additional trials, and a denial could force a strategic pivot or partnership. According to a report by Biospace, Summit has already faced skepticism from analysts who question whether PFS alone justifies approval. A regulatory setback would likely trigger a sharp decline in share price and erode investor confidence in the company's ability to execute.

Conclusion: Calculated Gamble or Regulatory Reckoning?

Summit's BLA gamble reflects a calculated bet on the FDA's evolving risk-benefit framework. While the agency's recent approvals suggest a path to authorization, the lack of OS data remains a critical vulnerability. Investors must weigh the potential for a breakthrough approval against the likelihood of post-approval constraints or outright rejection.

In the end, the outcome hinges on whether the FDA views ivonescimab's PFS benefits as sufficient to justify its risks-a decision that could redefine the regulatory playbook for oncology drugs in the post-OS era.