ALK in oncology
First Post from The Alkhemist’s Kugelrohr
This will be a space where I share reflections on drug discovery, commentary on the evolving landscape of biotech and innovation, occasional deep dives into scientific history, light-hearted ruminations, and conversations with fellow alchemists in our podcast The Alkhemist’s Glove Box, and hopefully some engaging discourse with others in the field.
We’re kicking it off with one of those targets you hear about in precision oncology all the time — one I’ve had the privilege of working on firsthand:
ALK in Precision Oncology: A Journey of Innovation
Since its discovery in 1994, the ALK pathway has become a pivotal focus in the advancement of precision oncology. Over the decades, groundbreaking therapies have emerged — and recent studies spotlight just how far we’ve come.
💊 Lorlatinib's Impact
The Phase 3 CROWN study revealed that 60% of patients with ALK-positive advanced NSCLC remained progression-free after five years on lorlatinib, compared to 8% with crizotinib. Notably, lorlatinib also reduced the risk of brain metastasis progression by 94% — a transformative leap for CNS-compromised patients.
Sources: Translational Lung Cancer Research, Pfizer, Reuters
📖 Want a patient-friendly overview? Check out this plain language summary of the CROWN study here: https://www.tandfonline.com/doi/abs/10.2217/fon-2021-0904?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed
🧪 Emerging Therapies: Navigating Resistance and Next-Gen ALK Inhibition
Nuvalent’s NVL-655 is showing promising results in overcoming resistance mutations and managing CNS disease. This brain-penetrant, selective ALK inhibitor was intentionally engineered to address both on-target resistance and off-target liabilities observed with earlier-generation TKIs.
Preclinical and early clinical data support its ability to maintain potency across diverse resistance mutations, while minimizing CNS-related adverse effects — a differentiator thought to stem from reduced off-target activity, particularly at TRKB【PMID: 38477329】.
Despite lorlatinib’s remarkable CNS efficacy — including a 94% reduction in brain metastasis progression and durable five-year PFS — resistance remains inevitable in many patients. Research groups are actively developing inhibitors to target these post-treatment resistance mutations, highlighting a real-world challenge in the therapeutic landscape.
Lorlatinib Resistance: A Closer Look
Resistance mechanisms to lorlatinib can be broadly categorized as follows:
These mutations present a significant therapeutic challenge, as they can drastically reduce sensitivity to all currently approved ALK TKIs.
Bypass signaling: EGFR, MET, KRAS, HER2/3, AXL, or NF2-mediated mTOR activation
Phenotypic transformation: EMT or small cell lung cancer (SCLC) transformation
These off-target mechanisms often require combination approaches or a complete shift in therapeutic strategy.
Clinical Implications and What Comes Next
Identifying the underlying resistance mechanism is critical. Techniques such as repeat biopsy and next-generation sequencing (NGS) of tumor tissue or circulating tumor DNA (ctDNA) play a pivotal role in guiding subsequent treatment decisions.
Looking ahead, fourth-generation ALK inhibitors — designed specifically to overcome compound resistance mutations — are in preclinical or early clinical stages. Combinatorial strategies that pair ALK TKIs with inhibitors of bypass pathways or immunotherapies may also offer renewed hope for durable disease control.