![Whole exome sequencing is becoming more available to patients and will help them distill the sequencing data to candidate genes and link them with therapies. [NCI]](https://www.insideprecisionmedicine.com/wp-content/uploads/2019/01/596.jpeg "Whole exome sequencing is becoming more available to patients and will help them distill the sequencing data to candidate genes and link them with therapies. [NCI]")
Patients with therapy-resistant cancers show improved outcomes if their treatments are personalized according to the molecular profile of their cancer, according to a new study published in NatureMedicine by researchers from the University of California, San Diego (UCSD) School of Medicine.
“Cancer treatments have evolved from indiscriminate cytotoxic agents to selective genome- and immune-targeted drugs that have transformed the outcomes of some malignancies. Tumor complexity and heterogeneity suggest that the ‘precision medicine’ paradigm of cancer therapy requires treatment to be personalized to the individual patient. To date, precision oncology trials have been based on molecular matching with predetermined monotherapies. Several of these trials have been hindered by very low matching rates, often in the 5–10% range, and low response rates. Low matching rates may be due to the use of limited gene panels, restrictive molecular matching algorithms, lack of drug availability, or the deterioration and death of end-stage patients before therapy can be implemented,” the investigators wrote.
“We hypothesized that personalized treatment with combination therapies would improve outcomes in patients with refractory malignancies. As a first test of this concept, we implemented a cross-institutional prospective study that used tumor DNA sequencing and timely recommendations for individualized treatment with combination therapies. We found that administration of customized multidrug regimens was feasible, with 49% of consented patients receiving personalized treatment. Targeting of a larger fraction of identified molecular alterations, yielding a higher ‘matching score’, was correlated with significantly improved disease control rates, as well as longer progression-free and overall survival rates, compared to targeting of fewer somatic alterations.
“Our findings suggest that the current clinical trial paradigm for precision oncology, which pairs one driver mutation with one drug, may be optimized by treating molecularly complex and heterogeneous cancers with combinations of customized agents.”
“Response rates to therapies that target one alteration can be low and not durable. Our approach went beyond targeting a single alteration,” said first author and co-principal investigator Jason K. Sicklick, MD, associate professor of surgery at UCSD School of Medicine and surgical oncologist at Moores Cancer Center at UCSD Health. “In collaboration with a multi-specialty team of oncology experts, we formulated a personalized combination therapy for each patient. With this approach, we saw an increased response rate, as well as improved overall survival and progression-free survival in patients who were highly matched to treatment versus those who were unmatched or less well-matched.”
In general, patients considered highly matched were those who had more than 50% of their tumor mutations matched to drugs.
Of the patients treated who were highly matched with combination treatments that targeted multiple alterations, 50% saw their disease respond compared to 22% that were unmatched or less well matched.
The prospective navigation trial (Investigation of Profile-Related Evidence Determining Individualized Cancer Therapy or I-PREDICT) enrolled patients with previously treated metastatic cancers at either Moores Cancer Center or Avera Cancer Institute in Sioux Falls, SD.
Molecular data, including genomic profiling using next-generation sequencing technology developed by study collaborator Foundation Medicine, was gathered for each patient and presented to a molecular tumor board consisting of oncologists, pharmacologists, cancer biologists, geneticists, surgeons, radiologists, pathologists, and bioinformatics experts who focused on creating customized, multidrug combinations to target a majority of the genomic alterations in each patient’s tumors.
The study consented 149 participants with metastatic, treatment-refractory disease, and, of these, 73 (49%) were matched to a therapy. Sixty-six were unable to be treated on the study, most commonly because their disease progressed too rapidly and they were placed in hospice or died, reflecting the advanced nature of their diseases.
“The percentage of patients matched was much higher than in most precision medicine studies because we implemented a team who instituted immediate review of genomic results, as well as navigators who helped patients and physicians access clinical trials, and off-label FDA-approved drugs,” said Shumei Kato, MD, assistant professor of medicine at UCSD School of Medicine and one of the lead investigators.
The therapies ultimately administered to each of the 83 treated patients were based on the treating oncologists’ choice and an individual patient’s preference. Only 10 patients had completely unmatched treatment. Seventy-three of the patients and their treating physicians chose a personalized, combination therapy that was matched to genomic alterations. The drugs included gene product-targeted drugs, hormone therapies, immunotherapies, and chemotherapies.
“Having 50% of patients with heavily pretreated disease responding when highly matched speaks to the importance of personalized, precision medicine combination approaches,” said senior author and co-principal investigator Razelle Kurzrock, MD, director of the Center for Personalized Cancer Therapy at Moores Cancer Center. “Our next step is to determine if we can increase the benefit rate further if this strategy is instituted earlier in the course of the disease.”
Patient outcomes were monitored until the disease progressed, treatment was no longer tolerated, or the patient died.
“Personalized, multi-drug therapies have not been used as standard treatment because there are concerns about the safety of administering drug combinations that have not been previously studied together,” said Sicklick. “Yet personalized combinations are necessary since no two tumors are exactly the same and so no two regimens will be the same. Our findings demonstrate that this approach is feasible and safe when patients are monitored closely and started on reduced doses.”
Researchers say larger follow up studies are needed to confirm the findings.
