Molecularly targeted therapies are increasingly demonstrating clinical relevance in cancer treatment, marking a significant shift towards precision medicine. Recent data presented at ASCO 2024 and in peer-reviewed publications highlight the evolution and efficacy of these targeted approaches across various cancer types.
Advancements in NSCLC Treatment
In non-small cell lung cancer (NSCLC), notable progress has been made with third-generation ALK tyrosine kinase inhibitors (TKIs). The phase 3 CROWN study (NCT03052608) revealed impressive 5-year survival data for lorlatinib (Lorbrena) compared to the first-generation agent crizotinib (Xalkori) in previously untreated, advanced ALK-positive NSCLC. With a median follow-up of 60.2 months, the median progression-free survival (PFS) for patients treated with lorlatinib had not been reached, while it was 9.1 months for those treated with crizotinib (HR, 0.19; 95% CI, 0.13-0.27). The 5-year PFS rate for lorlatinib was 60%, compared to only 8% for crizotinib.
Furthermore, the phase 3 LAURA trial (NCT03521154) demonstrated the benefits of adjuvant osimertinib (Tagrisso) following chemoradiation for stage III EGFR-mutated NSCLC. At 12 months, 74% of participants receiving adjuvant osimertinib were alive and progression-free, compared to 22% in the placebo group.
Immunotherapy in Rectal Cancer
Neoadjuvant checkpoint inhibitors are showing promising results in mismatch repair-deficient locally advanced rectal cancer. The phase 2 NICHE trial (NCT03026140) reported a 95% major pathological response rate, with 68% of treated patients achieving a complete pathological response. These outcomes suggest the potential for avoiding major surgery in this patient population, significantly altering therapeutic paradigms and future research strategies.
Targeted Therapies in Hematologic Malignancies
In hematologic malignancies, the precision medicine paradigm is also evident. A randomized phase 3 trial (NCT04971226) compared asciminib (Scemblix), a BCR::ABL1 inhibitor, with investigator-selected TKIs in newly diagnosed chronic myelocytic leukemia. At 48 weeks, a major molecular response was observed in 67.7% of patients treated with asciminib, compared to 49% in the investigator-selected group (P < .001). Additionally, asciminib was associated with a lower percentage of grade 3 or greater toxicities and fewer discontinuations of trial-directed therapy.
Another randomized phase 3 trial (NCT03589326) compared ponatinib (Iclusig) with imatinib (Gleevec) as initial therapy for Philadelphia chromosome-positive acute lymphoblastic leukemia. Patients receiving ponatinib experienced a superior rate of achieving a minimal residual disease-negative clinical state, at 34.4% versus 16.7% for imatinib (P = .002). The toxicity profiles for the two agents were similar.
The Future of Precision Medicine
These advancements underscore the rationality of the precision medicine paradigm in antineoplastic drug development. This strategy involves translational preclinical investigation and subsequent clinical trials. Even when a particular approach becomes standard of care, ongoing research efforts may lead to its substitution by more effective and safer regimens.
