Implications of Technologic Advances in the Era of Precision Oncology

Educational Objectives

The goal of this program is to improve the use of targeted therapy and personalized medicine in patients with cancer. After hearing and assimilating this program, the clinician will be better able to:

1. Use drugs with tissue-agnostic approvals in cancer treatment.
2. Recognize factors influencing next-generation precision oncology success.

Summary

Introduction: goals of precision oncology (PO) or targeted oncology — to maximize clinical efficacy, minimize adverse effects, and reduce economic burden; ≈200 new oncology drugs have been approved by the US Food and Drug Administration (FDA) between 1998 and 2022, 43% of which are PO therapies (requiring biomarker testing); Horak et al (2024) — on sequencing solid tumors, biomarker findings eligible for targeted therapies have increased from 9% (2017) to 31.6% (2022), while nonactionable oncogenic alterations have decreased from 44% to 22.8%

Site-agnostic approvals: current targets of site-agnostic FDA approvals in cancer — high tumor mutational burden (TMB), deficient mismatch repair, microsatellite instability (MSI), NTRK fusions, RET fusions, BRAF V600E mutations, fibroblast growth factor receptor alterations, and human epidermal growth factor receptor-2 (HER2)-positivity; drugs are now being approved for specific cancer-causing mutations or alterations, regardless of the site of origin

Response to site-agnostic drugs: certain mutations predict a stronger benefit from a drug that targets the mutation in some cancer types than others; single-agent BRAF inhibitors (effective in other cancers) have no activity in V600E-mutated metastatic colorectal cancer as they upregulate the epidermal growth factor receptor (EGFR) pathway (addition of an EGFR inhibitor improves clinical efficacy); considering drug combinations may be more beneficial than sequential targeted agents

Personalized drug combinations: may be needed to mitigate clonal evolution and resistance; Adashek et al (2023) equated the “whack-a-mole” approach in precision medicine to “slaying the mythical 9-headed Hydra” wherein severing one head inevitably resulted in the regrowth of 2 heads; combination therapies (multiple drugs) may help combat the heterogeneity of cancer

The American Society of Clinical Oncology (ASCO) provisional clinical opinion (Chakravarty et al [2022]): patients with metastatic cancer should undergo genomic sequencing if the presence of ≥1 genomic alteration has regulatory approval to guide the use of (or exclusion from) treatments (lower level evidence); multigene panel-based assays should be used if >1 biomarker-linked therapy is approved for the patient’s disease; in patients without tissue-based genomic test results (ie, inadequate tissue biopsy) treatment may be based on actionable alterations identified in circulating tumor DNA (ctDNA); site-agnostic approvals provide a rationale for genomic testing for all solid tumors

Recommendations from the European Society for Medical Oncology (Pascual et al [2022)]: ctDNA assays — evidence shows the clinical utility of ctDNA assays for genotyping advanced cancers; ctDNA is especially useful in the absence of tissue; it has lower sensitivity for gene fusions and copy number events and has a potential for false positives (because of clonal hematopoiesis); it has the potential for capturing intrapatient tumor heterogeneity; evidence for use of ctDNA for early cancer detection is lacking but holds considerable promise

Recent ASCO recommendation for ctDNA testing in breast cancer (BC): elacestrant has been approved for ESR1-mutated metastatic BC; ESR1 mutations develop because of resistance during treatment and are typically undetectable in the primary tumor (requiring real-time testing with tumor progression); per the Expert Panel, blood-based ctDNA testing is preferred to tissue-based genomic profiling because it has greater sensitivity

The rapid pace of scientific breakthroughs in genomics and PO: keeping up is a challenge; many targeted therapy drugs are now approved to treat non-small cell lung cancer (NSCLC); ASCO lung cancer “living” guidelines — first- and second-line treatment guidelines for NSCLC (in the presence and absence of driver mutations) are updated every 3 mo; an ASCO guideline application is available to make it more user-friendly; newer real-time artificial intelligence (AI)-based applications are being developed to make the diagnostic and treatment recommendations more accessible

Clinical practice gaps affecting implementation of personalized medicine in NSCLC: 64.4% of eligible patients with advanced or metastatic NSCLC did not benefit from targeted therapies because of testing issues (50%) or not receiving recommended treatments despite positive biomarker results (29%); clinical practice gaps were seen at multiple steps along the PO pathway, eg, inadequate specimens, inappropriate testing

Laboratory navigator pilot studies: American Society for Clinical Pathology pilot study (Pineault et al [2024]) — aimed to improve biomarker testing operations with navigators educated in biomarker testing (who can suggest further tests [to the clinicians] because of the presence of potentially actionable findings); Association of Cancer Care Centers — is assessing the performance metrics of navigators with a focus on financial assistance (ie, insurance approvals and patient copays) to determine how to facilitate test ordering and payment with a patient-centric approach

Advancing PO: the speaker proposes that AI will help with closing the knowledge gap in PO; however, additional costs may apply to obtain real-time updates; innovative trial designs and regulatory approaches are needed to keep pace with the scientific advances in PO to provide broad and early access to potentially lifesaving drugs

Challenges in drug approvals in PO: as biomarkers become more specific, eligible populations become rarer, and large phase-3 randomized controlled trials (RCTs) become difficult to conduct; high response rates in initial single-arm studies can limit the ability to enroll patients in subsequent RCTs; small patient populations limit the amount of safety data available for new drugs; evaluation of companion diagnostics adds complexity to expedited FDA-approval in PO

Ongoing research: the FDA’s expedited programs include Fast Track, Breakthrough Therapy, Priority Review, and Accelerated Approval; making the promising drugs available while the RCTs continue to prove long-term endpoint is important for patients with cancer; optimizing dose — the FDA suggests that defining optimal dosing of targeted agents should not be based on maximum tolerated dose (MTD); it is possible to have a major effect on the target without significant toxicity; several FDA projects are ongoing, eg, Project Optimus (for drugs in the approval pathway), Project Renewal (for approved drugs), Project Pragmatica (pragmatic RCTs are required to optimize the dose of the individual drugs used in combination therapy), ASCO TAPUR trial, the SWOG Pragmatica-Lung, and the NCI-MATCH trial

ASCO TAPUR trial: FDA-approved drugs are being repurposed for new cancer types with the same genomic marker; pembrolizumab (PEMBRO) was the first drug that had a tissue-agnostic approval for MSI-high cancers and later TMB-high cancers; however, patients with BC were not included in the data presented to the FDA before the approval; PEMBRO was indicated for triple-negative and programmed death-ligand 1-positive metastatic BC; however, good response was seen in TMB-high BC and HER-2-negative BC; long-term disease control was found outside of triple-negative; thus, TMB could be used outside of the already approved label in metastatic BC for PEMBRO

Factors influencing next-generation PO success: include the discovery of new actionable disease characteristics, the rapid, accurate, and comprehensive diagnosis of complex phenotypes within each patient, novel clinical trial designs and regulatory paths, and global access to novel targeted anticancer therapies for all patients

Barriers: include limited access to the diagnostic tools, limited accessibility and affordability of the drugs, limited availability of trained health care providers (to interpret the diagnostic results and prescribe the drugs), and limited infrastructure and resources to support PO; success in PO means matching the right (clinically available) therapy to the right patient at the right time

Readings

Adashek JJ, Subbiah V, Westphalen CB, et al. Cancer: Slaying the nine-headed hydra. Ann Oncol. 2023;34(1):61-69. doi:10.1016/j.annonc.2022.07.010; Aiman W, Ali MA, Jumean S, et al.BRAF inhibitors in BRAF-mutated colorectal cancer: A systematic review. J Clin Med. 2023;13(1):113. Published 2023 Dec 25. doi:10.3390/jcm13010113; Chakravarty D, Johnson A, Sklar J, et al. Somatic genomic testing in patients with metastatic or advanced cancer: ASCO Provisional Clinical Opinion [published correction appears in J Clin Oncol. 2022 Jun 20;40(18):2068. doi: 10.1200/JCO.22.01144]. J Clin Oncol. 2022;40(11):1231-1258. doi:10.1200/JCO.21.02767; First Tissue-Agnostic Drug Approval Issued. Cancer Discov. 2017;7(7):656. doi:10.1158/2159-8290.CD-NB2017-078; Horak P, Frohling S. Measuring progress in precision oncology. Cancer Discov. 2024;14(1):18-19. doi:10.1158/2159-8290.CD-23-1237; Marcus L, Fashoyin-Aje LA, Donoghue M, et al. FDA approval summary: Pembrolizumab for the treatment of tumor mutational burden-high solid tumors. Clin Cancer Res. 2021;27(17):4685-4689. doi:10.1158/1078-0432.CCR-21-0327; Moon H. FDA initiatives to support dose optimization in oncology drug development: The less may be the better. Transl Clin Pharmacol. 2022;30(2):71-74. doi:10.12793/tcp.2022.30.e9; Pascual J, Attard G, Bidard FC, et al. ESMO recommendations on the use of circulating tumour DNA assays for patients with cancer: A report from the ESMO Precision Medicine Working Group. Ann Oncol. 2022;33(8):750-768. doi:10.1016/j.annonc.2022.05.520; Pineault L, Valencia K, Buhay J, et al. Assessing the feasibility of a cancer biomarker testing navigator in the laboratory. Am J Clin Pathol. 2024;162(Supplement_1):S122-S122. doi:https://doi.org/10.1093/ajcp/aqae129.270; Rulten SL, Grose RP, Gatz SA, et al. The future of precision oncology. Int J Mol Sci. 2023;24(16):12613. Published 2023 Aug 9. doi:10.3390/ijms241612613.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. Gralow was recorded at the Cleveland Clinic Cancer Conference: Innovations in Multidisciplinary Care, held November 1-3, 2024, in Hollywood, FL, and presented by Cleveland Clinic. For information on upcoming CME activities from this presenter, please visit clevelandclinicmeded.com. Audio Digest thanks the speakers and Cleveland Clinic for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

Lecture ID:

ON160402

Qualifies for:

ABIM MOC, Clinical Pharmacology

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.