BARCELONA, SPAIN – Patients with advanced cancers receiving tumor-agnostic treatments based on the recommendations of a molecular tumor board had significantly better response rates and lived longer without the disease progressing than those receiving the standard of care in the ROME trial.
Still, MTB-directed treatment didn't lead to significantly better overall survival for patients, according to data presented Monday at the European Society for Medical Oncology Congress.
The ROME trial is a randomized, Phase II basket trial designed to evaluate the feasibility, efficacy, and safety of MTB-directed targeted drugs and immunotherapies compared to the standard of care in patients with advanced solid tumors. To enroll in the trial, patients were screened for actionable alterations by Foundation Medicine's tissue-based FoundationOne CDx and blood-based FoundationOne Liquid CDx.
Patients who had tumors bearing molecular markers that could be treated with approved drugs for their specific histology were excluded from the trial, which left those with tumors with molecular markers that could be targeted with off-label tissue-agnostic treatments. These patients were then randomized to the MTB arm or standard-of-care arm. In the MTB arm, a board of precision oncology experts determined the treatment patients received based on their tumor's biomarkers and regardless of histology, while in the standard-of-care arm, patients' doctors chose the standard treatment to give based on histology and in line with the Italian Association of Medical Oncology guidelines.
Currently, biomarker-informed targeted treatments and immunotherapies are available for a minority of cancer patients. European regulators have approved treatments that oncologists can prescribe refractory cancer patients based only on molecular markers, like NTRK fusions, and regardless of tumor histology, but, for the most part, biomarker-directed precision medicines are available only for histology-specific indications. The ROME investigators hypothesized, though, that cancer patients should benefit from treatment based on the genomic profile of their tumors regardless of histology, and they wanted to measure the extent of this benefit compared to the standard of care, particularly when the precision treatments were recommended by an expert body, like an MTB.
The researchers screened nearly 1,800 patients with recurrent or metastatic solid tumors including breast, gastrointestinal, non-small cell lung, and other cancers between November 2020 and December 2023. Patients could fail screening for various reasons, including not having any targetable genomic alterations or having rare mutations lacking functional significance. To be eligible, patients must have also completed at least one line of prior treatment but no more than two.
Patients also had to test positive for certain molecular abnormalities, for example, DNA damage repair gene mutations, high tumor mutational burden, BRAF V600E mutations, and NTRK fusions, and others, that can be targeted by targeted drugs or immunotherapies on the market.
In the MTB arm, the board recommended patients receive one of 26 targeted agents or three immunotherapies based on their tumor biomarker. Once patients progressed on either arm, however, they could cross over to the other arm of the trial. Patients underwent molecular profiling again at progression.
The ROME trial design, to an extent, assessed the value an MTB added to patient care. Andrea Botticelli, professor of oncology at Sapienza University of Rome who presented the ROME trial data, said the MTB played a crucial role in the trial. "The role of the molecular tumor board was to combine all of the available information, both clinical information and genomic information, in order to define the most effective and safe therapy or combination strategy," he said.
The MTB comprised members of the trial steering committee who were experts in oncology, pathology, biology, and immunology. The board met weekly and took into consideration both single-gene and multi-gene alterations, as well as factors such as actionability and mechanisms of resistance when making recommendations for each patient, Botticelli said. They used the COSMIC, OncoKB, and ClinVar databases to evaluate the role of mutations detected in patients' cancers and determined their actionability based on the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) scale. The board first decided whether the patient could enroll in the trial and then recommended biomarker-informed tissue-agnostic treatments for those not in the standard-of-care arm.
The MTB discussed 897 patient cases and randomized 400 patients. The three most common biomarkers among enrolled patients were high tumor mutational burden, PIK3CA alterations, and ERBB2 alterations. In the MTB arm, the board assigned 55 percent of patients to targeted therapy, 30 percent to immunotherapy, and 7 percent to a combination of targeted therapy and immunotherapy. The most frequently assigned targeted therapies included Bristol Myers Squibb's CTL-4 targeted monoclonal antibody Yervoy (ipilimumab) combined with its checkpoint inhibitor Opdivo (nivolumab), Roche's investigational AKT inhibitor ipatasertib, Incyte Biosciences' FGFR2 kinase inhibitor Pemazyre (pemigatinib), Roche's HER2-targeted antibody-drug conjugate Kadcyla (trastuzumab emtansine), and Roche's PD-1 inhibitor Tecentriq (atezolizumab) combined with ipatasertib.
The trial met its primary endpoint and showed that patients responded better to MTB-directed therapy than on standard therapies. In the MTB arm, the overall response rate was 17 percent, with 2.5 percent having a complete response and 14.5 percent having a partial response; 18 percent had stable disease, and 65 percent had progressive disease. In the standard-of-care arm, meanwhile, 9.5 percent of patients had a partial response, 17.5 percent had stable disease, and 73 percent had progressive disease.
Patients on MTB-directed treatments also had better median progression-free survival, 3.7 months versus 2.8 months in the standard-of-care group. One year after beginning therapy, 22 percent of patients in the MTB group had not had their disease progress, compared to 7 percent in the standard therapy group.
Ultimately, though, patients on MTB-directed therapy didn't live significantly longer than those on standard treatments. Patients in the MTB group had numerically greater median overall survival at 9.2 months versus 7.6 months in the standard therapy group, but the difference was not statistically significant. "However," Botticelli noted, "52 percent of patients in the standard-of-care group were treated with targeted therapy in the crossover phase," which could have affected the statistical analysis.
Despite the lack of a statistically significant overall survival advantage in the MTB arm in the ROME trial, the researchers concluded that previously treated patients with advanced solid tumors benefited when an MTB recommended treatments based on their comprehensive genomic profiling results. "It's clear the [molecular tumor board] is playing a crucial role in the mutation tumor-agnostic approach and that new trial designs are needed to provide working models to expedite patient access to targeted therapy," Botticelli said.
Basket trials have, by design, provided opportunities for evaluating tissue-agnostic therapeutic strategies based on molecular profiling, though they don't always involve an MTB. In the US National Cancer Institute's Molecular Analysis for Therapy Choice (NCI-MATCH) trial launched in 2015, researchers studied the benefits of targeted therapies assigned based on genomic profiling of their tumors. However, instead of an MTB, NCI-MATCH used a computational platform called MATCHBOX to assign patients to treatment arms based on their genetic alterations.
Several studies exploring the value of MTBs in directing precision cancer care are underway. For example, in the TCF-001 TRACK (Target Rare Cancer Knowledge) study, for example, the TargetCancer Foundation is using a virtual MTB to identify treatments for patients with seldom-seen tumors. At the Dartmouth Cancer Center, researchers are having an MTB recommend treatments to patients in a clinical trial and surveying their doctors about how the MTB's recommendations impacted their treatment decisions. In the PRiMAL study, researchers at the University of Kentucky are comparing usual care against MTB-directed care in newly diagnosed NSCLC patients.