Genomically Matched Cancer Therapies Only as Good as Supporting Evidence

Patients with advanced/refractory cancers treated with genomically matched therapies had better overall survival only when the treatments had support from prospective studies, a large multicenter cohort study from Australia showed.

Median overall survival (OS) improved from 12.8 months with unmatched therapies to 21.2 months with evidence-based therapies selected with guidance from the TOPOGRAPH precision oncology database. In contrast, use of biomarker-matched therapies supported only by lower-tier “investigational” evidence (such as studies in other tumor types/preclinical work) did not significantly improve OS versus unmatched therapies (14.5 vs 12.8 months). Patients who received therapies repurposed from other cancer types based solely on a biomarker (no directly applicable evidence) also did not live longer than patients who received unmatched therapies.

The results support an evidence-based approach to prioritize genomically guided therapies for cancer, concluded Frank P. Lin, MBChB, PhD, of the University of Sydney, and colleagues in JAMA Oncology.

“We observed a 40% reduction in the risk of death associated with the receipt of genomic-matched therapy in the clinically active tier group [TOPOGRAPH tiers 1-3A] after accounting for confounders and time-related biases,” the authors stated. “Conversely, we found no OS difference in patients who received treatment matched to the investigational therapy tier groups overall (tiers 3B and 4).”

“The observation of a lack of survival difference regarding drug repurposing (tier 3B) was particularly noteworthy, as inferring treatments based on biomarkers alone from evidence extrapolated from [other cancer types] is commonly used in the absence of histotype-specific trials or regulatory approvals.”

Qualified Support

The author of an accompanying editorial agreed that the results provide strong support for use of an evidence-based framework to support precision oncology treatment strategies.

“By transforming the binary question of [biomarker] actionability into a nuanced inquiry about evidence strength, the investigators provide oncologists with a sophisticated decision-making tool beyond simple lists of druggable variants,” asserted Vivek Subbiah, MD, of the Sarah Cannon Research Institute in Nashville, Tennessee.

“For patients with rare and refractory cancers, genomic profiling offers hope, but transforming hope into extended survival requires distinguishing genomic possibilities from validated therapeutic strategies,” he added.

Subbiah noted that the Australian study included patients treated from 2016-2021, when many targetable genomic variants had few if any available therapies, a limitation that likely “attenuated the observed benefits.” Additionally, the lack of benefit for tier 3B and 4 matches might also have reflected the drugs available during the study period.

The ability to detect and study genetic aberrations in tumors paved the way to development of an untold number of new cancer therapies over the past two decades. Increasingly, multigene panel testing has been used to identify treatment options for patients with advanced cancers and who have exhausted standard therapies, Lin and colleagues noted.

Multiple studies have shown improved disease control with therapies selected on the basis of biomarkers, but results have been inconsistent, in large part because of lack of a standardized definition of “actionability” of genomic alterations. To gain insight into the issue, the authors analyzed data from the screening component of the Australian Molecular Screening and Therapeutics (MoST) study, a nationwide precision oncology program that uses genomic profiling of archival tissue to identify actionable biomarkers for patients with advanced or rare cancers.

The analysis included adults enrolled in the MoST program from June 2016 to December 2021 and followed through July 2022. Investigators compared survival in patients who received therapies selected on the basis of TOPOGRAPH guidelines evidence levels 1-3A versus those treated with therapies supported only by investigative studies or using repurposed drugs (evidence tiers 3B/4).

Study Details

Data analysis encompassed 3,383 patients, 3,003 of whom had at least one genomic biomarker for which a tier 1-4 therapy could be matched. The 3,003 patients included 1,270 (37.5%) with clinically active biomarkers (tiers 1-3A).

The study population was stratified into two cohorts: 2,065 who received no further systemic therapies and 1,318 who received systemic therapy after genomic profiling. In general, patients who received no therapy were older, higher risk, and had worse prognosis.

The total population had a median follow-up of 22.6 months and a median OS of 11.3 months. Overall, patients who received no additional therapy after genomic profiling had a median OS of 8.2 months versus 14.1 months for those who received systemic therapy.

Among the 3,003 patients with a tier 1-4 genomic alteration, those who did not receive additional therapy had a significantly shorter OS (7.1 vs 30.1 months, HR 2.39, 95% CI 1.93-2.97, P<0.001). Among patients who did receive additional therapy, receipt of an unmatched treatment was associated with a median OS of 13.7 months versus 20.3 months for those who received a tier 1-4 matched therapy (HR 1.43, 95% CI 1.13-1.82, P<0.001).

Of the 1,318 patients who received additional therapy, 382 received at least one line of systemic therapy matched to a tier 1-4 biomarker and the rest received unmatched therapies. Overall, patients who received a matched therapy had a significantly longer OS (16.3 vs 13.4 months, HR 0.76, 95% CI 0.65-0.88, P<0.001).

Subsequently, 116 patients received at least one therapy matched to clinically active biomarkers (tier 1-3A), which was associated with a 46% reduction in the survival hazard (95% CI 0.41-0.71, P<0.001) as compared with patients who received unmatched therapies. Patients who received only therapies supported by investigational studies had a 14% reduction in the survival hazard, which did not differ significantly from the unmatched group (95% CI 0.72-1.02).

An analysis of patients who had at least one tier 1-3A biomarker showed that those who received matched therapies had a 40% reduction in the survival hazard versus those who received unmatched therapy. Patients who received tier 1-2 matched therapies had better survival than those who received tier 3 therapies.

“A consistent, tier-based OS difference was observed in an exploratory tier-matched analysis selecting only the same therapies in both matched and unmatched groups,” the authors added.

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