Molecular matching makes an IMPACT
HOUSTON—Precision medicine efforts are underway across the globe, but it could be argued that few are quite as extensive as the IMPACT (Initiative for Molecular Profiling and Advanced Cancer Therapy) study by The University of Texas MD Anderson Cancer Center, retrospective results for which were presented at the 2018 American Society for Clinical Oncology (ASCO) Annual Meeting. The study looked to determine the results of matching patients to therapies based on tumor-specific gene mutations across tumor types, with participants receiving either matched targeted therapy (MTT) or non-matched treatment (NMT). As seen with long-term data, the MTT group had a three-year overall survival (OS) of 15 percent, compared to 7 percent in the NMT group, and a 10-year OS of 6 percent, compared to 1 percent in the NMT group.
A total of 3,743 MD Anderson patients were enrolled in IMPACT from 2007 to 2013, with all patients referred to MD Anderson’s Phase 1 program with end-stage disease. Median age was 57 years, with women representing 61 percent of participants and men representing 39 percent. Breast, lung, melanoma, gastrointestinal and gynecologic cancers were the most common in this group, with 77.7 percent of patients' cancer types falling into those categories.
All IMPACT participants underwent molecular testing, with 1,307 found to have at least one molecular alteration, 711 receiving MTT (with or without chemotherapy) and 596 receiving NMT. Of those who received MTT, the majority received an investigational drug under evaluation in a clinical trial, while others received a U.S. Food and Drug Administration-approved targeted therapy commercially approved for another indication. Earlier in the course of the study, patients were tested for mutations in individual genes, according to an ASCO press release, but as the study progressed it switched to next-generation sequencing to test 20 to 50 genes at at time.
Dr. Apostolia M. Tsimberidou, professor of Investigational Cancer Therapeutics at MD Anderson and principal investigator for IMPACT, presented the findings at ASCO.
“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 Tsimberidou. “Our findings show that molecular testing of tumors using 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.”
“When we opened IMPACT, it was viewed as incredibly novel. Because of the variability, frequency and rarity of alterations in specific solid tumor types, it was thought it would be difficult to use molecular testing for clinical trial selection, without taking into consideration any specific characteristics,” she added. “However, gleaning from our Gleevec-CML experience, we hypothesized that genetic and molecular analysis of solid tumors also could enable the selection of optimal therapy for patients with solid tumors.”
Of the patients who received MTT, median progression-free survival (PFS) was four months, with median OS of 9.3 months. Those who received NMT saw median PFS of 2.8 months and median OS of 7.3 months.
IMPACT's investigators used trial data to create a prognostic score that could predict OS, and MD Anderson reported that the absence of liver metastases, normal LDH levels, normal functional status, albumin levels and platelet counts are all independent factors for longer OS—as was receiving MTT. Accordingly, liver metastases, elevated LDH levels, poor functional status, low albumin levels, elevated platelet counts and an age of 60 years or older were all associated with shorter OS. Molecular alterations in the PI3K/AKT/mTOR pathway and NMT also registered as independent factors for shorter OS.
“When IMPACT first opened, we tested for no more than one-to-two genes,” Tsimberidou noted. “Now patients are being tested for hundreds of actionable genes, amplifications and mutations, as well as for immune markers. Ideally, in the future, patients’ tumor testing and cell-free DNA analysis will become the standard of care at the time of diagnosis, in hopes of making a difference for patients upfront, especially in those with hard-to-treat cancers.”
A follow-on study is already underway—IMPACT2, a randomized Phase 2 study comparing PFS in MTT patients versus NMT patients. MD Anderson announced an alliance in August 2014 with Foundation Medicine to conduct IMPACT2. Foundation Medicine's FoundationOne is a validated, comprehensive genomic profiling assay that can detect all classes of genomic alterations in solid tumors across 315 cancer-related genes and 28 genes that are often rearranged in cancer. An MD Anderson press release noted a prediction that more patients will be eligible for MTT in IMPACT2 compared to IMPACT1 due to FoundationOne's more comprehensive abilities compared to the previously used molecular testing.
“Based on the IMPACT1 data, a validated, comprehensive profiling approach has already been adopted by many academic and community-based oncology practices. They use this approach for select groups of cancer patients for whom existing diagnostic and treatment options are inadequate, such as non-small cell lung cancer, cancer of unknown primary and rare tumors,” Dr. Vincent Miller, chief medical officer of Foundation Medicine, said in a 2014 release detailing the launch of IMPACT2. “This study has the potential to yield sufficient evidence necessary to support broader adoption across most newly diagnosed metastatic tumors. We’re pleased to partner with MD Anderson, who is uniquely positioned to execute this study given their clinical trials expertise.”