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Article

Oncology Live®

Vol. 25/No. 12
Volume25
Issue 12

Molecularly Targeted Therapeutics Are Precisely Aimed

Maurie Markman, MD, details how the precision-medicine paradigm is a highly rational platform for antineoplastic drug development.

Maurie Markman, MD

Maurie Markman, MD

Presentations at the recent 2024 American Society of Clinical Oncology Annual Meeting (ASCO 2024) once again impressively demonstrated the clinical relevance of the antineoplastic drug development process widely known as precision cancer medicine.

Long gone are debates in the medical literature regarding what one commentator labeled the “precision-oncology illusion,”1,2 and it is most unlikely in the future that a small, randomized phase 2 study that declares “off-label use of molecularly targeted agents should be discouraged” will find more than limited interest within the oncology community.3

Today, molecularly based antineoplastic therapy targeted to subsets of organ-specific cancers has become standard of care (SOC) in multiple cancer types, with the number of regulatory agency–approved indications rapidly increasing. In addition, over the past few years, several targeted therapeutics have achieved tumor-agnostic approval, meaning their delivery is to be based on the documented presence of a specific molecular abnormality within the cancer of an individual patient rather than on the site of origin of the malignancy.4

But perhaps the most interesting observation in the presented meeting abstracts, as well as in a number of recent peer-reviewed publications, is the evolution of the precision medicine process with the development of second- and third-generation agents that have been shown to be more effective and possibly safer (more precise) than the original drugs that changed the particular cancer’s management paradigm.

For example, consider the simply stunning 5-year survival data from a phase 3 trial (NCT03052608) reported at ASCO 2024 for patients with previously untreated, advanced ALK-positive non–small cell lung cancer (NSCLC) treated with the third-generation ALK tyrosine kinase inhibitor (TKI) lorlatinib (Lorbrena) vs the first-generation agent in this molecular targeting category, crizotinib (Xalkori).5 With a median follow-up of 60.2 months, the median progression-free survival (PFS) for patients treated with lorlatinib had not been reached compared with 9.1 months with crizotinib (HR, 0.19; 95% CI, 0.13-0.27).

The 5-year PFS rate for the newer agent was 60% vs 8% with the older drug. To be crystal clear, this last sentence must be repeated. The 5-year PFS rate observed in this trial for patients with ALK-positive advanced NSCLC was 60%.5

In addition to the ongoing replacement of SOC molecular agents, the demonstrated clinical indications for their use continue to expand. For example, consider the recently published trial data revealing the benefits of administering osimertinib (Tagrisso), a known, highly active agent in EGFR-mutated NSCLC, in the adjuvant setting following chemoradiation for stage III EGFR-mutated disease.6

Impressively, 74% of participants in the phase 3 LAURA trial (NCT03521154) who received adjuvant osimertinib were alive and had not experienced disease progression at 12 months compared with only 22% of individuals randomly assigned to placebo.6

This commentary discussing precision medicine in solid tumor oncology would not be complete without mentioning the rapidly evolving and simply stunning results observed with the use of neoadjuvant checkpoint inhibitors in the management of mismatch repair–deficient locally advanced rectal cancer. For example, a recent report of the phase 2 NICHE trial (NCT03026140) involving more than 100 patients in this setting revealed a 95% major pathological response rate, with 68% of treated patients achieving a complete pathological response with this therapeutic approach.7 Although the long-term results associated with the early use of immunotherapy in this patient population remain to be fully defined, including the realistic potential for the avoidance of major surgery, these reported outcome data have certainly modified both existing therapeutic paradigms and substantially altered discussions regarding future research strategies.

The message of rapidly evolving and increasingly effective cancer therapeutics based on the precision medicine drug development paradigm is also evident in hematologic malignancies, as emphasized by the recent report of a randomized phase 3 trial (NCT04971226) in newly diagnosed chronic myelocytic leukemia where asciminib (Scemblix) was directly compared with an “investigator-selected [TKI],” a setting that may arguably be considered the poster child for the clinical utility of molecularly targeted cancer treatment.8

Asciminib, a BCR::ABL1 inhibitor, was designed to both increase efficacy and reduce the off-target toxicity effect of the earlier-generation agents. The study results revealed that at 48 weeks a major molecular response was observed in 67.7% of individuals treated with asciminib compared with 49% for the investigator-selected population (P<.001). In addition, the percentage of individuals experiencing grade 3 or greater toxicities or requiring discontinuation of trial-directed therapy was lower in the asciminib-treated group.

In another recently reported randomized phase 3 trial (NCT03589326), ponatinib (Iclusig), a newer BCR::ABL1 inhibitor with broader molecular activity, was compared with first-generation imatinib (Gleevec) as initial therapy of Philadelphia chromosome–positive acute lymphoblastic leukemia.9 Patients randomly assigned to ponatinib experienced a superior rate of achieving a minimal residual disease–negative clinical state, at 34.4% vs 16.7% for patients taking imatinib (P=.002). The toxicity profiles for the 2 agents were similar.

In conclusion, the very specific point being highlighted in this commentary is that the precision medicine paradigm is a highly rational platform for antineoplastic drug development.This strategy includes both translational preclinical investigation as well as the subsequent initiation and completion of clinical trials based on these observations.

Further, even when a particular approach has successfully achieved the lofty position of becoming a component of the SOC, future research efforts following the precision medicine strategy may lead to its substitution by an alternative, more effective (and potentially safer) regimen.

References

  1. Prasad V. Perspective: the precision-oncology illusion. Nature. 2016;537(7619):S63. doi:10.1038/537S63a
  2. Subbiah V, Kurzrock R. Debunking the delusion that precision oncology is an illusion. Oncologist. 2017;22(8):881-882. doi:10.1634/theoncologist.2017-0040
  3. Le Tourneau C, Delord JP, Gonçalves A, et al; SHIVA Investigators. Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced cancer (SHIVA): a multicentre, open-label, proof-of-concept, randomized, controlled phase 2 trial. Lancet Oncol. 2015;16(13):1324-1334. doi:10.1016/S1470-2045(15)00188-6
  4. Gouda MA, Nelson BE, Buschhorn L, Wahida A. Tumor agnostic precision medicine from the AACR GENIE database: clinical implications. Clin Cancer Res. 2023;29(15):2753-2760. doi:10.1158/1078-0432.CCR-23-0090
  5. Solomon BJ, Liu G, Felip E, et al. Lorlatinib vs crizotinib in treatment-naïve patients with advanced ALK+ non-small cell lung cancer: 5-year progression-free survival and safety from the CROWN study. J Clin Oncol. 2024;42(suppl 17):LBA8503. doi:10.1200/JCO.2024.42.17_suppl.LBA8503
  6. Lu S, Kato T, Dong X, et al; LAURA Trial Investigators. Osimertinib after chemoradiotherapy in stage III EGFR-mutated NSCLC. N Engl J Med. 2024;391(7):585-597. doi:10.1056/NEJMoa2402614
  7. Chalabi M, Verschoor YL, Batista PB, et al. Neoadjuvant immunotherapy in locally advanced mismatch repair-deficient colon cancer. N Engl J Med. 2024;390(21):1949-1958. doi:10.1056/NEJMoa2400634
  8. Hochhaus A, Wang J, Kim DW, et al; ASC4FIRST Investigators. Asciminib in newly diagnosed chronic myeloid leukemia. N Engl J Med. 2024;391(10):885-898. doi:10.1056/NEJMoa2400858
  9. Jabbour E, Kantarjian HM, Aldoss I, et al. Ponatinib vs imatinib in frontline Philadelphia chromosome-positive acute lymphoblastic leukemia: a randomized clinical trial. JAMA. 2024;331(21):1814-1823. doi:10.1001/jama.2024.4783
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