Jacob J. Adashek, DO of the Moffitt Cancer Center explains the ESMO 2020 Abstract – Personalized molecularly matched therapies for carcinomas of unknown primary is associated with improved outcomes.
Context
CUP accounts for 2-5 percent of the world’s overall cancer diagnoses and represents a
Heterogeneous cancer community.
Combination chemotherapy with modest reaction rates is the preferred treatment.
(20 percent-40 percent). The median overall survival remains low (6-15 months), however.
Empirical treatments have been performed (e.g. carboplatin / paclitaxel, cisplatin / gemcitabine).
Centered on tissue-of-origin gene expression compared to tissue-specific therapies
Profiling; There was no clinical advantage in randomized trials.
While some studies have explored matched, molecular-based targeted therapy
Analysis needs further investigation.
"¢ 97 samples of tumors: 59 women, 38 men
Next-generation sequencing (NGS) of 74 tissues
"¢ 72 DNA (cfDNA) cell-free sequencing
Age 63 (range, 21-95) median
"¢ Median number of NGS alterations: 4 (0-25 range), cfDNA: 2 (0-9 range)
For 62 patients, clinical findings were evaluable.
Immunohistochemistry of PD-L1, condition of microsatellite instability (MSI), and tumor
TMB (mutation burden) was also evaluated.
Genomic modifications have been “matched” to drugs that have targeted the particular modification
For all patients, matching scores were determined.
"¢ The number of planned deleterious genomic changes divided by the total number of deleterious changes
Outcomes
Genes that are most often altered:
"¢ NGS: 55.4 percent TP53; 24.3 percent CDKN2A; 20.3 percent KRAS
CfDNA: TP53 61.1 percent; 22.2 percent KRAS; 16.7 percent PIK3CA;
Of the 55 patients tested for PD-L1, 30.9% were positive (defined as about 1% for tumor [n = 16]).
Lymphocytes infiltrating the tumor [n = 1])
9.4% (6/64) of tumors had high TMB (⇠20 mutations / mb), while 3.6% (2/55) had high TMB (⇠20 mutations / mb).
MSI-High-High
High matching score > 50 percent (n=15) vs. low matching score > 50 percent (n=47) [including 25 without no matching score = 50 percent (n=47)] Therapy matched]
Median survival without progression: 10.4 vs. 2.8 months (95 percent CI 0.11-0.64; HR 0.27; 95 percent CI 0.11-0.64; HR 0.27;
(p=0.002) P=0.002)
Median total survival: 15.8 months vs. 6.9 months (95 % CI 0.17-1.16; HR 0.45; P=0.09)
Level of disease control (stable disease of about 6 months plus partial or full response)
Strong Matching Score vs. Group with Low Matching Score (71% vs. 24%; P=0.003)
Findings
Identifying these modifications means that certain CUP patients may have targeted opportunities for treatment.
Personalized combination therapies with high degrees of molecular matching to genomic alterations (Matching Score > 50 percent) were correlated with enhanced outcomes among patients with CUP.
In order to determine whether matched targeted therapy (including combination therapies) could enhance outcomes in CUP patients over standard-of-care chemotherapy regimens, future prospective trials are required.