Puma Biotechnology's AACR Breakthrough: A New Era for HER2-Targeted Cancer Therapies?

The cancer therapeutics space just got hotter. At the American Association for Cancer Research (AACR) Annual Meeting 2025, Puma Biotechnology (NASDAQ: PBYI) dropped a bombshell: promising early data for its combination therapy of neratinib (NERLYNX®) with trastuzumab deruxtecan (T-DXd/ENHERTU®). This isn’t just lab talk—this is a potential game-changer for patients with hard-to-treat HER2-altered solid tumors. Let’s break it down.

The Clinical Data: A Strong Start in a Tough Field

The Phase I trial evaluated neratinib + T-DXd in 20 patients with HER2-altered cancers, including pancreatic, ovarian, and gastroesophageal cancers—cancers known for their resistance to treatment. Here’s what stood out:
- Safety First: While side effects were common (nausea, diarrhea, fatigue), severe events (Grade 3+) were manageable. Notably, the most concerning toxicity—pneumonitis—was only Grade 1 in three patients.
- Efficacy Sparks: Of 15 evaluable patients, 4 achieved partial responses, including three of five pancreatic cancer patients. One pancreatic patient saw tumor shrinkage lasting 13+ cycles—a rare victory in a disease with a 5-year survival rate of just 12%.
- Recommended Phase II Dose: The highest dose tested (neratinib escalating to 240 mg daily) was selected, setting the stage for larger trials.

Dr. Andrew Davis, the lead researcher, called the results “promising,” while Puma’s CEO Alan Auerbach emphasized the combo’s potential in cancers “where there are no good options.”

Why This Matters: HER2-Altered Tumors Are a Growing Market

HER2-positive breast cancer therapies alone are a $3 billion market in the U.S., and it’s expanding. But Puma’s combo isn’t just for breast cancer—it’s targeting any solid tumor with HER2 alterations, including the deadly pancreatic and ovarian cancers.

The data also comes at a pivotal time. T-DXd, developed by Daiichi Sankyo and AstraZeneca, recently won FDA approval for HER2-low breast cancer (January 2025), a far broader patient pool. Combining it with Puma’s neratinib—a drug already approved for HER2-positive breast cancer—could create a synergistic “one-two punch” to block HER2 signaling and deliver cytotoxins to tumors.

The Investment Case: Pipeline Catalysts and Financials

Puma’s stock has already been on a tear, rising 35% over six months (as of early 2025) thanks to strong NERLYNX sales and positive alisertib trial data. The AACR data adds fuel to the fire:
- Phase II Trial Underway: Part 2 of the trial, enrolling 12 patients for pharmacodynamic analysis, began in March 2025. If successful, this could lead to Phase III trials by 2026, with an NDA filing possible by 2028.
- Financial Strength: Puma holds $96.8 million in cash, enough to fund operations through 2025. Guidance projects $183–190 million in 2025 revenue, driven by NERLYNX sales and pipeline progress.
- Strategic Partnerships: The trial was backed by the National Cancer Institute (NCI) and Daiichi Sankyo—a nod to Puma’s credibility in oncology.

Risks and Challenges

• NERLYNX Sales Declines: Q2 2024 NERLYNX sales dropped to $44.4 million (vs. $51.6M in 2023), signaling reliance on the pipeline to offset stagnation.
• Safety Scrutiny: While pneumonitis was mild in this trial, T-DXd’s profile includes severe ILD risks in other studies. Larger trials must confirm safety.
• Big Pharma Competition: Roche’s T-DM1 and Enhertu dominate the ADC space, but Puma’s combo targets a unique niche—HER2-altered tumors beyond breast cancer.

The Bottom Line: A High-Reward, High-Risk Play

Puma’s AACR data isn’t a slam dunk—it’s early, and pancreatic cancer is brutal—but the potential is undeniable. If this combo works in Phase II/III trials, Puma could carve out a $500M+ annual revenue stream in a $3B+ market.

Investors should watch for:
- Phase II data in 2025, which could validate efficacy in pancreatic/ovarian cancers.
- NERLYNX sales trends—if they stabilize, Puma’s cash runway stays intact.
- Partnership news: AstraZeneca/Daiichi Sankyo’s support could lead to broader collaborations.

At current prices (~$12.50 as of May 2025), PBYI trades at a P/S ratio of 1.2x, cheap for a biotech with such a high-risk/high-reward pipeline. The stock could double if Phase II hits home runs—but a misstep could sink it.

Final Takeaway: Buy the Dip, but Buckle Up

Puma’s AACR data is a major catalyst for investors willing to bet on breakthrough oncology therapies. For those with a high-risk tolerance and a long-term view, this is a “Buy the Dip” opportunity. But remember: cancer drugs are a rollercoaster. If you’re in, stay informed—and keep your seatbelt fastened.

Action Alert: Puma’s stock is volatile, but with Phase II data coming soon, now’s the time to consider a position—if you can stomach the swings.