Researchers at University of California San Diego School of Medicine have shown that it is possible to treat cancer with individualized combination therapies matched to each tumor’s unique molecular profile without compromising patient safety.
The findings “provide a blueprint for the future of personalized or individualized precision medicine for patients with cancer,” said the study’s senior author Jason Sicklick, MD, professor of surgery and pharmacology at UC San Diego School of Medicine and surgical oncologist at UC San Diego Health.
“When we started this trial, we didn’t even know if personalizing cancer treatment was feasible or safe,” Sicklick told Inside Precision Medicine. “We have now shown that it is possible and have highlighted the importance of targeting more than a single driver mutation in the management of complex cancers.”
At present, precision oncology treatments focus on using single molecular biomarkers to select matched monotherapies for specific cancers such as EGFR inhibitors for EGFR-mutant lung cancer. While these have undoubtedly improved outcomes, advanced cancers are molecularly complex, and treatments could be optimized further by targeting multiple molecular alterations at once.
To investigate the feasibility of this approach, Sicklick and colleagues carried out the I-PREDICT study, in which 210 patients (median age 62 years, 58% women) with advanced cancer were treated according to the results of next generation sequencing (NGS) carried out on tumor tissue and/or blood samples. The most common cancers were colorectal (14.0%), pancreatic (8.1%), ovarian (7.6%), and sarcomas (7.6%).
The researchers report in the Journal of Clinical Oncology that patients had a median of five pathogenic alterations per tumor (range, 0-20) and approximately 95% of patients had tumors with unique molecular landscapes.
The NGS results were analyzed by a molecular tumor board, and treatments were administered according to the board’s recommendations.
In all, 157 different regimens were prescribed including 132 regimens that were administered to just one patient each. Of note, 66% of the treatments given did not have established safety data or recommended dosing at time of administration.
To address this, patients who were given two or more drugs previously unstudied in combination started treatment on lower than FDA-approved doses of each drug. The doses were then adjusted to a tolerance level during careful follow-up that included weekly clinic visits to begin with.
Unexpectedly, the researchers found that participants given previously unstudied regimens had significantly lower rates of serious drug-related toxicities than those given established regimens, at 6.5% versus 15.5%. They believe this could be because patients given previously unstudied regimens received lower doses.
There were no significant differences in adverse event rates according to the number drugs used or how well the biomarkers matched the treatment given, which was calculated by a matching score (number of pathogenic alterations targeted divided by the total number of pathogenic alterations).
However, patients with a high matching score (>50%) had significantly better outcomes than those with a low (≤50%) matching score, including a higher disease control rate (DCR; 60 vs 29%) and longer median progression-free survival (PFS; 7.2 vs 3.1 months) and overall survival (19.1 vs 10.0 months).
Sicklick noted that “all the tools are available now to implement a treatment protocol for individually dosed drug combinations on a larger scale since we are just using FDA-approved drugs.” But he acknowledged that even though some advanced cancer patients at UC San Diego are now being treated according to an N-of-1 approach, shifting how physicians think about prescribing treatments on a wider scale will require additional validation studies.
The team is therefore working to secure funding for the STRIPe (STudy of Real-world Individualized Precision-oncology), which has a randomized design and will compare individually matched combination therapy with standard care.
“Our findings demonstrate that precision oncology at the individual level is achievable,” Sicklick concluded. “When every patient’s treatment is guided by their tumor’s distinctive DNA, we can treat cancer with better accuracy.”
