IMPACT: Matching Treatment and Molecular Testing Extends Survival in Advanced CancerWeb Exclusives
A new retrospective analysis presented at ASCO 2018 lends support to precision medicine in cancer. In the Initiative for Molecular Profiling and Advanced Cancer Therapy (IMPACT) clinical trial, selecting a targeted therapy based on patients’ tumor molecular analyses independently predicted longer overall survival (OS) compared with nonmatched therapy across a diverse set of advanced tumor types. Apostolia Maria Tsimberidou, MD, PhD, Professor, Department of Investigational Cancer Therapeutics, M.D. Anderson Cancer Center, Houston, presented the study results.
“Our findings show that molecular testing of tumors with next-generation sequencing can be used to optimize therapy and should be taken into consideration when selecting therapy for patients with difficult-to-treat cancers,” said Dr Tsimberidou.
The IMPACT Study
In the analysis, which included patients who exhausted standard treatment options or had rare, incurable cancers, the 10-year OS rate was 6% for patients who received matched therapy compared with 1% for those receiving nonmatched therapy.
IMPACT included 3743 patients with cancer who had molecular testing and who presented to M.D. Anderson between 2007 and 2013. Of these, 1307 patients had ≥1 targetable molecular alterations; 54.4% received a matched targeted therapy; and 45.6% received a nonmatched therapy. The most common tumor types were gastrointestinal (24.2%), gynecologic (19.4%), breast (13.5%), melanoma (11.9%), and lung (8.7%).
Patients who had received matched treatment were most often referred to M.D. Anderson’s phase 1 clinical trial for treatment with an investigational therapy; a minority of patients received a commercially available targeted therapy approved for another indication. Patients had a median of 4 previous therapies, and some patients had up to 16 treatments. Only 2.8% of patients (with rare, incurable cancers) had not received any previous treatment.
In the early years of the study, tumors were tested for mutations in individual genes, whereas in the later years of the study (until the end of 2013), next-generation sequencing was used to analyze 20 to 50 different genes at once.
Matching Treatment Improves Survival
The group with treatment that matched genomic testing had an objective response rate of 16.2%, and an additional 18.7% of patients had stable disease lasting ≥6 months. By contrast, in the nonmatched group, these percentages were 5.4% and 14.7%, respectively. Disease control rates in the 2 groups were 34.9% with matched treatment and 20.1% without matched treatment (P <.001).
Significant improvements in progression-free survival (PFS) and OS were also observed in the matched group. The median PFS was 4.0 months in the matched group compared with 2.8 months in the nonmatched group (hazard ratio [HR], 0.67; P <.001). The median OS was 9.3 months in the matched group and 7.3 months in the nonmatched group (HR, 0.72; P <.001).
Of the 1307 patients with at least 1 molecular alteration, the 3-year OS rate was 15% in the matched treatment group versus 7% in the nonmatched group. The OS in the matched group plateaued starting at 38 months (11% of patients were still alive at that point).
Matched targeted therapy was found to be an independent factor that predicts longer OS in multivariate analysis. In the multivariate analysis, nonmatched therapy increased mortality risk by 30% (P <.001), as did the presence of PI3K, AKT, or mTOR mutations (P <.001).
Targeting the MEK/RAF or RET pathways with RET or MEK/RAF inhibitors was correlated with higher rates of complete response plus partial remission and standard disease at ≥6 months, PFS, and OS compared with all other therapies (P <.001).
“This is the first and largest study, with the longest follow-up, to assess the impact of precision medicine approaches on survival across multiple cancer types,” said Dr Tsimberidou.
ASCO Expert Catherine S. Magid Diefenbach, MD, Clinical Director Lymphoma, Perlmutter Cancer Center at New York University Langone Health, New York City, commented on the implications of this study.
“This is the first and largest study that shows that matching treatments to genetic mutations in tumors in patients with advanced cancer improves survival. Most of these patients received drugs that were either FDA approved or were in advanced clinical trials, so people did not have to go out and reinvent the wheel to treat these patients in a completely new way,” said Dr Diefenbach. “Precision medicine allows us to focus on what the genetic aberrations are in the tumor itself, not on the neighborhood of the tumor and not on the growth kinetics of the tumor. As such, this method of molecular profiling tumors and treating on the basis of actionable mutations is the wave of the future,” she added.
Anxiety is a common symptom in patients with advanced cancer, and is associated with reduced quality of life, increased symptom burden, poor medication adherence, and suboptimal treatment decisions at the end of life. Anxiety also tends to cluster with disease- and treatment-related side effects such as fatigue, pain, breathlessness, nausea, vomiting, and sleep disturbance.
Genetic alterations in molecular pathways are involved in tumor development, survival, and progression. Precision cancer medicine is about using the cancer genome to guide treatment decisions, according to Christine M. Walko, PharmD, BCOP, Personalized Medicine Pharmacologist, Personalized Medicine Clinical Service, and Chair, Clinical Genomic Action Committee, Moffitt Cancer Center, Tampa, FL.