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Continuous monitoring of circulating tumor DNA may guide treatment of advanced melanoma
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CHICAGO — Monitoring circulating tumor DNA during treatment for advanced melanoma may assistant in identifying those patients likely to benefit from dabrafenib alone or with trametinib, according to an analysis of data from the phase 3 COMBI-d trial presented at ASCO Annual Meeting.
This appeared particularly true for patients with high baseline lactate dehydrogenase, an established prognostic factor in this setting.
“Our study offers firm evidence that tracking this genetic information may be helpful in identifying patients whose cancers shrink and who survive longer as a result of a particular drug regimen,” senior study researcher David Polsky, MD, PhD, the Alfred W. Kopf, MD, professor of dermatologic oncology at NYU Langone Health, said in a press release.
The analysis included 345 patients with unresectable or metastatic melanoma treated with dabrafenib (Tafinlar, Novartis) alone or with trametinib (Mekinist, Novartis) in the phase 3 COMBI-d trial and who underwent BRAF V600E/V600K circulating tumor DNA (ctDNA) plasma measurements at baseline and week 4.
Researchers assessed the plasma samples using mutation-specific droplet digital polymerase chain reaction assays (Bio-Rad Laboratories), categorizing the results as positive or negative using a threshold of 0.25 copies/mL.
Most patients (n = 320; 92.7%) had detectable baseline ctDNA. However, baseline ctDNA measurements were not associated with survival.
Almost all patients showed a decrease in ctDNA by 4 weeks of therapy.
Of the 224 patients with 4-week measurements, 128 remained positive for ctDNA and 96 were negative. Patients who remained positive showed significantly shorter median PFS (7.4 months vs. 13 months; HR = 1.68; 95% CI, 1.24-2.27) and OS (15.3 months vs. 27.9 months; HR = 1.64; 95% CI, 1.2-2.25) than patients who became ctDNA negative.
Overall, 201 patients had detectable baseline ctDNA that could be compared with paired 4-week measurements. Of them, 121 (60%) remained positive for ctDNA at 4 weeks, and 80 (40%) were negative. Those who became negative showed a significant improvement in median PFS (12.9 months vs. 7.1 months; HR = 0.55; 95% CI, 0.39-0.76) and median OS (28.2 months vs. 14.6 months; HR = 0.56; 95% CI, 0.4-0.79).
Researchers also compared outcomes according to ctDNA among patients with low (n = 143) and high (n = 81) baseline lactate dehydrogenase.
Of those with high baseline lactate dehydrogenase, 64 remained positive and 17 were negative for ctDNA. Of those with low baseline lactate dehydrogenase, 64 remained positive and 79 became ctDNA negative.
Patients with high baseline lactate dehydrogenase showed a particularly significant benefit if they became negative for ctDNA (median PFS for ctDNA positive vs. negative, 5.5 months vs. 10.3 months; HR = 1.99; 95% CI, 1.08-3.64; median OS, 10.8 months vs. 21.1 months; HR = 2.38; 95% CI, 1.24-4.54).
The corresponding differences for patients with low lactate dehydrogenase did not reach statistical significance.
Typically, patients with melanoma are assessed for disease progression with CT scans every 3 months. However, this ctDNA blood test assessment may allow for more frequent monitoring, with quickly available results, according to Polsky.
Researchers next plan to analyze this approach over a longer period, and they are planning a clinical trial that would determine whether making treatment decisions based on ctDNA monitoring improves survival outcomes.
“If further testing proves successful, monitoring blood samples for BRAF could give us an early indication of whether or not we need to adjust a patient’s treatment plan,” he said in the press release. – by Alexandra Todak
Reference:
Syeda MM, et al. Abstract 9510. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.
Disclosures: Polsky reports consultant/advisory roles with MolecularMD and Novartis, research funding to his institution from Bio-Rad Laboratories and Novartis, and travel expenses from Bio-Rad Laboratories. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Omid Hamid, MD
The ASCO presentation by Polsky and colleagues sets a standard for advanced metastatic melanoma surveillance which currently lacks validated blood-based biomarkers.
Although serum lactate dehydrogenase is utilized as a staging marker, it is an unreliable on-treatment biomarker. ctDNA functions through monitoring plasma levels of associated mutations found in solid tumors. ctDNA can be utilized, in the absence of a tissue biopsy, to guide therapy through detection of mutations in solid tumors and for the characteristics of resistance at progression. More importantly, baseline levels of ctDNA in patients with BRAF mutations have been associated with initial prognosis. Changes to undetectable levels of ctDNA can also provide prognostic value.
In this companion protocol to COMBI-D, researchers monitored 201 patients with detectable baseline ctDNA throughout treatment with BRAF/MEK inhibition. Results confirmed that elevated levels of ctDNA correlated with OS, independent of other variables. Undetectable levels at week 4 of therapy were associated with OS, a doubling of survival and PFS.
Interestingly, this mimics the data presented in prior presentations. It is revolutionary to know that 5 ml of plasma can monitor mutation levels and deliver prognostic information. Mutations such as TERT, NRAS and BRAF can be exploited to assist in clinical decision-making in the adjuvant and metastatic setting. In the future, an on-therapy undetectable value that increases to detectable may signal a need to change therapy, or at least image the patient earlier than expected. The inability to completely eliminate ctDNA in a patient may initiate an addition to current therapy or a therapeutic switch at plateau.
Analysis of ctDNA has also been valuable in differentiating between progression and pseudo progression in patients on immune checkpoint inhibitor therapy. ctDNA also has been shown to have predictive capabilities in the adjuvant setting.
Limitations of this process exist as not all tumors with mutations have detectable ctDNA (93% in this study) and monitoring intracranial disease has not been proven. At this time, ctDNA is available through multiple commercial platforms making it accessible to the masses. Its strength as a dynamic prognostic biomarker make it a promising alternative to tissue biopsy and frequent imaging. This benefit can relate to all solid tumors and not just melanoma.
References:
Lee JHJ, et al. Abstract 9546. Presented at: ASCO Annual Meeting; June 2-6, 2017; Chicago.
Lee JHJ, et al. Abstract 9581. Presented at ASCO Annual Meeting: May 31-June 4, 2019; Chicago.
Lee JHJ, et al. Abstract 9583. Presented at: ASCO Annual Meeting; June 2-6, 2017; Chicago.
Tan L, et al. Ann Oncol. 2018;doi:10.1093/annonc/mdy269.
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