Quantifying the Expanding Landscape of Clinical Actionability for Patients with Cancer

Abstract

There is a continuing debate about the proportion of cancer patients that benefit from precision oncology, attributable in part to conflicting views as to which molecular alterations are clinically actionable. To quantify the expansion of clinical actionability since 2017, we annotated 47,271 solid tumors sequenced with the MSK-IMPACT clinical assay using two temporally distinct versions of the OncoKB knowledge base deployed 5 years apart. Between 2017 and 2022, we observed an increase from 8.9% to 31.6% in the fraction of tumors harboring a standard care (level 1 or 2) predictive biomarker of therapy response and an almost halving of tumors carrying nonactionable drivers (44.2% to 22.8%). In tumors with limited or no clinical actionability, TP53 (43.2%), KRAS (19.2%), and CDKN2A (12.2%) were the most frequently altered genes.

Significance: Although clear progress has been made in expanding the availability of precision oncology-based treatment paradigms, our results suggest a continued unmet need for innovative therapeutic strategies, particularly for cancers with currently undruggable oncogenic drivers. See related commentary by Horak and Fröhling, p. 18. This article is featured in Selected Articles from This Issue, p. 5.

Figure 1.

Biomarker-driven FDA drug approvals between 1998 and 2022. A, Consort diagram detailing the categorization of FDA-approved oncology drugs between June 1998 and November 2022. Definitions for all categories are detailed in the methods. B, Number of first-in-class (black) and mechanistically distinct/follow-on/resistance (gray) FDA-approved precision oncology drugs between June 1998 and November 2022. The number of genomic biomarkers (genes and MSI-H and TMB-H) included in the “Indications and Usage” section of the FDA drug labels in drugs approved per year is shown with the blue line. *Arsenic trioxide, approved in 2000, is considered a follow-on drug after the first-in-class drug tretinoin approved in 1995 for PML–RARA fusion-positive acute promyelocytic leukemia. **Homologous recombination repair (HRR) genes include ATM, BARD1, BRIP1, CDK12, CHEK1/2, FANCL, PALB2, RAD51B/C/D, RAD54L. ^∧Biomarkers specified as patient eligibility criteria in FDA drug labels of preexisting FDA-approved drugs.

Figure 2.

Analysis of the clinical actionability of solid tumor samples in 66 tumor types from the MSK-IMPACT cohort (n  =  47,271). A, Frequency of actionable mutations pan-cancer in tumor samples annotated by OncoKB version March 2017 (2017v1.8) versus OncoKB version October 2022 (2022v3.17). B, Actionable mutations and associated gene prevalence per cancer types in 2017 versus 2022. HNSCC, squamous cell carcinoma of the head and neck; SCLC, small cell lung cancer; RCC, renal cell carcinoma. C and D is for samples with levels 3B, 4, or samples with nonactionable drivers, variants of unknown significance (VUS) or no alteration as highest actionability (n = 30,320). C, Percent of samples with an oncogenic alteration in the indicated gene. Genes altered in >2% of samples are shown. D, Percent of samples with an oncogenic alteration in at least one gene in the indicated gene category. Genes in each category are shown in Supplementary Table S4 and include genes altered in >1% (n = 68) of indicated samples.