Clinical value of guideline recommended molecular targets and genome targeted cancer therapies: cross sectional study

Abstract

Objective: To assess the clinical benefit and actionability of molecular targets for genome targeted cancer drugs recommended for clinical practice by the National Comprehensive Cancer Network (NCCN).

Design: Cross sectional study.

Participants/setting: Genome targeted cancer drugs recommended by NCCN guidelines in the advanced setting.

Main outcome measures: Molecular target actionability was assessed using the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT). Clinical benefit of genome targeted oncology therapies was evaluated using the ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS). Molecular targets at ESCAT category level I associated with studies showing substantial clinical benefit by ESMO-MCBS (grades 4-5) were designated as high benefit, and those linked to studies achieving an ESMO-MCBS grade of 3 were categorized as being of promising but unproven benefit.

Results: 411 recommendations related to 74 genome targeted drugs targeting 50 driver alterations were examined. Most recommendations (346/411; 84%) were associated with clinical trials of various phases, but 16% (65/411) relied on only case reports or pre-clinical studies. However, clinical trials mostly comprised phase I or phase II (271/346; 78%), single arm (262/346; 76%) studies. The primary endpoint assessed in most trials was overall response rate (271/346; 78%) rather than survival. ESCAT tier I targetability encompassed 60% (246/411) of target recommendations, 35% (142/411) were classified as tier II or III, and 6% (23/411) had their relevance yet to be determined (tiers IV to X). When ESMO-MCBS was applied to 267 scorable trials, only 12% (32/267) showed substantial clinical benefit (grades 4-5) and 45% (121/267) were grade 3. When both frameworks were combined, 12% (32/267) of trials supported a determination of high benefit and 33% (88/267) indicated promising but unproven benefit. Of the 118 interventions endorsed by NCCN authors as preferred, 62 (53%) applied to treatments with high or promising but unproven benefit.

Conclusion: According to the ESCAT and ESMO-MCBS frameworks, about one eighth of genome based treatments for solid cancer were rated as likely to offer a high benefit to patients, whereas around a third were identified as offering a promising but unproven substantial benefit. Ensuring that NCCN recommendations are aligned with expected clinical benefits is crucial for promoting informed, evidence based, genomic guided treatment decisions.

Fig 1

Identification and selection of cancer drug recommendations identified in National Comprehensive Cancer Network (NCCN) guidelines. One recommendation can be supported by one or more articles. Guidelines included biliary tract cancers, bladder cancer, breast cancer, central nervous system cancers, cervical cancer, colorectal cancer, endometrial cancer, gastric cancer, gastrointestinal stromal tumor, head and neck - salivary gland tumors, hepatocellular carcinoma, melanoma, non-small cell lung cancer, neuroendocrine and adrenal tumors, ovarian cancer, soft tissue sarcoma, pancreatic adenocarcinoma, prostate cancer, testicular cancer, thyroid carcinoma, uterine cancer, and vulvar cancer

Fig 2

European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT) levels of evidence for molecular targets. Figure shows proportions of molecular targets falling into different ESCAT levels of evidence among genome targeted drugs recommended by National Comprehensive Cancer Network guidelines

Fig 3

Value of molecular targets recommended by National Comprehensive Cancer Network (NCCN) guidelines. Molecular targets associated with substantial clinical benefit by European Society for Medical Oncology - Magnitude of Clinical Benefit Scale (ESMO-MCBS) (grade 4 or 5 for those of non-curative intent) and qualifying for ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) tiers I-A, I-B, and I-C, were rated as high benefit genome based cancer treatments. Molecular targets achieving a grade 3 on ESMO-MCBS and qualifying for ESCAT tiers I-A, I-B, and I-C were classified as being of promising but unproven benefit