Nuvalent Faces "The Day of Reckoning"—The Hopes and Risks of the Next-Generation ROS1 Inhibitor

Table of Contents

1. Who is Nuvalent?

2. ROS1-Positive NSCLC: Current Status and Challenges of Rare Cancers

3. The Science of Zidesamtinib: The Art of TRK-Sparing Design

4. Overview and Latest Data of the ARROS-1 Trial

5. Dialogue with Regulatory Authorities and Approval Strategy

6. Stock Price Impact: Bull and Bear Scenarios

7. Competitive Comparison: Can It Beat Repotrectinib and Crizotinib?

8. Key Points for Investment Decisions and Risk Management

9. Conclusion—The Scope of "OnTarget 2026"

10. List of Reference Articles
    
    

1. Who is Nuvalent?

Founded in 2017, headquartered in Cambridge, Massachusetts, USA.Specializes in research and development, adopting a "virtual fabless" lightweight management style by outsourcing manufacturing. As of the end of March 2025, cash and cash equivalents are approximately $980 million, securing operational funds through 2027.filecache.investorroom.com



Pipeline Overview

• NVL-520 (ROS1)

• NVL-655 (ALK, 4th Generation)

• NVL-330 (HER2 Ex20ins Preclinical)

2. ROS1-Positive NSCLC: Current Status and Challenges of Rare Cancers

ROS1 fusion genes are recognized in **1-2% of NSCLC, with 40% having brain metastases at diagnosis, making them difficult-to-treat cases. Existing TKIs (crizotinib, entrectinib) face bottlenecks with CNS penetration and resistance mutations (G2032R)**. The efficacy of immune checkpoint inhibitors is limited, and expectations for new TKIs are high.onclive.com

3. The Science of Zidesamtinib: The Art of TRK-Sparing Design

Zidesamtinib binds to the ROS1 activation loop at sub-nanomolar concentrations, characterized by selectivity that "bypasses" TRK. It avoids neurotoxicity (such as sensory abnormalities) associated with TRK inhibition while ensuring blood-brain barrier permeability. Molecular modeling studies were published in Mol. Cancer Therapeutics in April 2025.investors.nuvalent.com

4. Overview and Latest Data of the ARROS-1 Trial

Trial Design: International multi-center, Phase 1/2, target enrollment 359. Primary endpoint is objective response rate (ORR), with secondary endpoints including PFS and CNS control rate.
Topline announced on June 24, 2025 (median follow-up 11.2 months):

• Q4 2025 to submit NDA

• Within 12 months of obtaining approval,initiate the first post-marketing survey—as declared.
  prnewswire.com

5. Dialogue with Regulatory Authorities and Approval Strategy

The FDA granted Breakthrough Therapy designation in 2024, along with Orphan Drug designation in the same year. Based on final data, they plan to apply for Priority Review, expecting a six-month reduction in standard review time. Negotiations for rolling review are ongoing with the European EMA.

6. Stock Price Impact: Bull and Bear Scenarios

• Bull Case: If ORR maintains published values and median PFS exceeds 18 months, first-year sales could reach $750 million, with a target stock price of $110.

• Bear Case: If safety signals manifest in the brain metastasis subset and ORR is revised downward, stock price could fall below $50.
  German Aktiencheck warns, "The direction will be determined by the day's price movement—a 'Binary Event'."aktiencheck.de

7. Competitive Comparison: Can It Beat Repotrectinib and Crizotinib?

| Item | Zidesamtinib | Repotrectinib | Crizotinib |
| CNS ORR | 50% | 34% | 7% |
| G2032R ORR | 72% | 28% | ND |
| TRK Inhibition | None | Present (Increased Side Effects) | None |


4th Generation ALK Inhibitor NVL-655 has commenced the Phase 3 Alecensa showdown trial ALKAZAR.oncologypipeline.com

8. Key Points for Investment Decisions and Risk Management

• Clinical Differentiation: CNS control power and efficacy against resistance mutations

• Regulatory Risk: Risk of inspection delays even with priority review

• Funding: Possibility of dilution with additional capital raising before and after approval

• Competitive Trends: Amgen's new ROS1/MET dual inhibitor enters Phase 1

9. Conclusion—The Scope of "OnTarget 2026"

Nuvalent aims for high clinical impact in the niche of "precision targeted drugs." If zidesamtinib is approved, NVL-655 in the ALK domain and NVL-330 in the HER2 domain will follow in a "wave-like offensive," potentially exponentially increasing corporate value. On the other hand, the risk of binary outcomes, inherent to the biotech sector, remains. Investors need to carefully assess the quality of data and the evaluation criteria of regulatory authorities.

List of Reference Articles

• Börse Global "Nuvalent Aktie: Entscheidungstag für Krebsmedikament" (2025-06-24)aktiencheck.de

• AInvest "Nuvalent’s Zidesamtinib: A Breakthrough in ROS1-Positive Lung Cancer" (2025-06-24)ainvest.com

• PR Newswire "Nuvalent Announces Timing of Pivotal Data for ARROS-1" (2025-06-24)prnewswire.com

• Molecular Cancer Therapeutics (2025-04-29) "Rational Design of Zidesamtinib"investors.nuvalent.com

• OncologyLive "ARROS-1 Trial of Zidesamtinib"on