Pralsetinib: The RET Precision-Targeted Therapy That Rewrites the Treatment History of Rare Cancers

Preface

In the realm of precision medicine, RET was once regarded as a "minor" target, as its mutation rate in solid tumors such as non-small cell lung cancer and thyroid cancer accounts for only 1%-2%. However, behind this seemingly small number lie countless patients who have been trapped in the dilemma of treatment. Due to the lack of highly effective specific drugs, these patients have long faced the challenges of limited treatment options and significant side effects. The advent of Prasugrel has completely rewritten this history. As a highly selective RET inhibitor, it is like a precisely guided "key" that directly targets the core target driving tumor growth. It not only brings unprecedented high response rates and durable survival benefits to patients, but also redefines the treatment standard for such rare cancers with excellent safety, becoming a paradigm of precision medicine benefiting minority groups.

Mechanism of action: Highly selective inhibition of RET targets

The core design of Pralatrexate lies in its high selectivity towards RET kinase, thereby surpassing traditional multi-kinase inhibitors in terms of efficacy and safety:

Potent inhibition: As an oral, potent, and highly selective RET tyrosine kinase inhibitor, pralatrexate exhibits a nanomolar half-maximal inhibitory concentration against both wild-type RET and various activating mutations, demonstrating significantly superior efficacy compared to multi-target drugs such as cabozantinib and vandetanib.

Excellent selectivity: Its inhibitory potency against RET is over 80 times that against VEGFR2, enabling precise blockade of the RET signaling pathway that drives tumor growth, while significantly reducing common serious adverse reactions such as hypertension, hand-foot syndrome, and proteinuria caused by off-target effects.

Overcoming drug resistance potential: It also exhibits inhibitory activity against common solvent-frontier mutations, including RET G810R/S/C, providing more possibilities for long-term treatment.

Penetrating the blood-brain barrier: Both preclinical and clinical data confirm its good permeability to the central nervous system, effectively controlling brain metastasis.

Clinical evidence: The ARROW study lays the foundation for efficacy

The efficacy of pralatrexate has been comprehensively validated in the pivotal Phase I/II ARROW study:

Initial treatment for RET fusion-positive advanced non-small cell lung cancer: The objective response rate reached 72%, the complete response rate was 11%, the median duration of response has not been reached yet, and the progression-free survival rate at 12 months was 82%. Among patients with measurable brain metastases, the intracranial objective response rate was 56%.

Patients with previously treated RET-positive advanced non-small cell lung cancer who had received platinum-based chemotherapy achieved an objective response rate of 61%, with a median duration of response of 22.3 months and a median overall survival of 44.3 months.

RET-mutant advanced medullary thyroid cancer: Among patients who had not received systemic treatment, the objective response rate was 71%; even for those who had undergone multi-kinase inhibitor treatment, the objective response rate still reached 60%, and the response was durable.

RET fusion-positive thyroid cancer: The overall objective response rate is as high as 89%, with a complete response rate of 10%, providing an important option for patients refractory to radioactive iodine treatment.

Safety characteristics: High selectivity leads to better tolerability

Thanks to its high selectivity for RET, the safety profile of Prasugrel is significantly improved compared to traditional multi-kinase inhibitors:

The most common treatment-related adverse events include elevated aspartate aminotransferase, anemia, constipation, hypertension, etc., most of which are grade 1-2.

The key grade 3 and above adverse events are primarily neutropenia (about 42%) and hypertension (about 14%), which can be managed through monitoring, dose adjustment, and supportive treatment.

Compared to traditional multi-kinase inhibitors, pralatrexate significantly reduces typical off-target toxicities such as hand-foot syndrome, hemorrhage, and proteinuria, offering superior overall tolerability and a lower rate of drug discontinuation due to adverse events.

Dosage and Administration and Patient Management

Standard dose: 400 mg orally, once daily, taken on an empty stomach.

Dose adjustment: Gradually reduce the dosage based on the severity of adverse reactions such as neutropenia, hypertension, and hepatotoxicity.

Important monitoring: Regular monitoring of blood routine, liver function, and blood pressure is required, with special attention given to patients at risk of bleeding.

Approved indications

Based on the ARROW study data, pralidoxime has been approved in multiple countries worldwide for:

RET fusion-positive metastatic non-small cell lung cancer (adult)

Advanced or metastatic RET-mutant medullary thyroid cancer (in adults and children over 12 years old) requiring systemic treatment

RET fusion-positive thyroid cancer (in adults and children over 12 years old) that requires systemic treatment and is refractory to radioactive iodine

Future outlook

Pralatrexate has ushered in a new era of RET-targeted therapy, yet there are still numerous directions worth exploring:

Overcome acquired resistance and develop a new generation of RET inhibitors.

Explore combination strategies with MEK inhibitors, immunotherapy, and other treatments.

Expand its application in other solid tumors with RET mutations (such as colorectal cancer and pancreatic cancer).

Explore the possibility of limited-course treatment and sustained remission after drug withdrawal in indolent tumors such as thyroid cancer.

Conclusion

The success of Prasugrel serves as a vivid footnote to the shift in cancer treatment from "broad-spectrum" to "precision". It is not only an effective drug, but also an innovation in treatment paradigm - demonstrating that even for rare genetic targets, breakthrough efficacy can be achieved through highly selective inhibition. From illuminating the "forgotten corners" to becoming the new standard in clinical treatment, Prasugrel has ignited tangible hope for patients with RET mutations. Looking ahead, with in-depth exploration of its resistance mechanisms and the development of next-generation drugs, the arsenal of therapeutic weapons targeting RET mutations will become increasingly abundant. As a pioneer and cornerstone in this field, Prasugrel's significance goes beyond the drug itself. It symbolizes the depth and boundaries of precision medicine, which are constantly expanding, engraving more possibilities for every unique individual.