In a randomised, multi-basket, phase II, Italian multicentre ROME study conducted among pretreated patients with metastatic cancer, targeted therapy, driven by comprehensive genomic profiling and molecular tumour board (MTB) activities, significantly improved overall response rate (ORR) and progression-free survival (PFS), with a notable long-term PFS benefit at 12 months and beyond. However, targeted therapy was not associated with overall survival (OS) benefit. In a high tumour mutational burden (TMB) subgroup, immunotherapy provided a significant PFS benefit among patients with both microsatellite instability (MSI)-high and microsatellite stable (MSS) tumours.
Toxicity profile in the targeted therapy and standard-of-care (SoC) groups were different, but both had a similar incidence of adverse events. The findings are reported at the ESMO Congress 2024 by Dr. Andrea Botticelli of the Department of Radiological, Oncological and Pathological Sciences, Sapienza Università di Roma, AOU Policlinico Umberto I in Rome, Italy, who pointed out that MTB is playing a crucial role in the mutational/tumour agnostic approach.
The authors explained in the background that historically, drug approval has been based on a tissue-specific model, initially guided by histology and later also by molecular biomarkers associated with specific cancer sites. Recently, the tumour agnostic model, driven by specific genomic alterations regardless of the tumour site or histology, has been applied for the approval of several drugs. The mutational model, guided by comprehensive genomic profiling and MTB activities, could help to overcome some limitations of previous models and allow for the selection of more effective targeted therapies.
Several clinical trials have been conducted and are still ongoing to evaluate the impact of precision oncology approaches based on genomic alterations on patients’ clinical outcomes. In the ROME study conducted among patients with advanced or metastatic solid tumours with no more than two previous lines of histology-based standard therapy, the study team performed comprehensive genomic profiling using the next-generation sequencing (NGS) with FoundationOne CDx on tissue samples and LiquidCDx on blood.
Once molecular alterations were identified in tumour tissue or liquid biopsy, that could potentially be targeted by drugs available within the study, the clinical case was reviewed by the MTB and the MTB then decided whether to enrol the patient and proceed with randomisation or to classify the case as a screening failure. At disease progression, crossover was planned. The primary endpoint was ORR. Secondary endpoints included PFS, OS, and safety.
Available targeted therapies in the study were erlotinib for EGFR mutations; trastuzumab, pertuzumab, T-DM1, lapatinib for ERBB2 amplification/mutations; everolimus for mTOR mutations and AKT mutations; vemurafenib and cobimetinib for BRAF mutations; alectinib and brigatinib for ALK translocations and RET alterations; pralsetinib and selpercatinib for RET alterations; palbociclib for CDK4/6 and CDKN2A/B alterations; ponatinib for BCR-ABL translocations; vismodegib for SMO/PTCH1 mutations; itacitinib for JAK mutations; pemigatinib for FGFR1/2/3 alterations; ipatasertib and alpelisib for PI3K, AKT and PTEN alterations; entrectinib for NTRK1/2/3 fusions and ROS1; tepotinib for METex14 and MET alterations; talazoparib for BRCA1/2 mutations and homologous recombination deficiency.
Available immune checkpoint inhibitors in the study were nivolumab, ipilimumab and atezolizumab in case of MSI and high TMB status; high TMB was defined as more than 10 mut/Mb in solid and/or liquid NGS.
The role of MTB was to combine all the available information, both clinical and genomic, to define the safest and most effective targeted therapies. The MTB considered both single gene and pathway alterations as molecular targets. Molecular alterations were evaluated using the COSMIC, OncoKB and ClinVar databases and actionability was assessed using the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT). When choosing targeted therapies, mechanisms of resistance were also considered.
From November 2020 to August 2023, a total of 1794 patients were screened and 897 discussed in MTB with 127 weekly MTB discussions resulting in 400 patients (22.5%) who were randomised 1:1 to targeted therapy at MTB choice or SoC at investigator choice. Targeted therapy was recommended to 221 patients (55%), immunotherapy to 153 patients (38%) and combination of targeted therapy plus immunotherapy to 26 patients (7%).
Median age of patients overall was 61 year (range, 22-85), most of the patients were Caucasian; 38 different histologies were enrolled, including colorectal cancer (16%), breast cancer (10%), gastric cancer (9%), glioblastoma (9%), biliary tract cancer (9%), non-small cell lung cancer (9%), ovarian cancer (5%), pancreatic cancer (4%), melanoma (3%), anal cancer (2%) and other (24%). Enrolment line was second- in 51% of patients and third-line in 49%. There were no imbalances between the groups.
The most common targetable genomic alterations were TMB-high (34%), PIK3CA/AKT/PTEN (19%), ERBB2 (14%), FGFR (8%) and MSI (4%). The most frequently assigned therapies were ipilimumab or nivolumab (37%), ipatasertib (16%), pemigatinib (8%), T-DM1 (8%), atezolizumab (6%) and ipatasertib (6%).
Global ORR was 13.3%, 9.5% in SoC group and 17% in group of patients treated by targeted therapy (p = 0.027). The median PFS in intention-to-treat population was 3.7 months (95% confidence interval [CI] 3.0-4.8) in targeted therapy group and 2.8 months (95% CI 2.5-3.0) in SoC (hazard ratio [HR] 0.64, 95% CI 0.51-0.80; p < 0.0001); 9-month PFS rate was 28.4% in targeted therapy group and 12.8% in SoC group, while 12-month PFS rate was 22.3% in targeted therapy group and 7.7% in SoC group. Median OS was 9.2 months for targeted therapy versus 7.6 months for SoC (HR 0.89, 95% CI 0.68-1.13 p = 0.299).
As an exploratory analysis, patients with TMB high or MSS tumours receiving targeted therapy (immunotherapy) had a median PFS of 3.6 months and a 12-month PFS rate of 32.7% compared to 2.8 months and 6.3% in the SoC group (HR 0.65, 95% CI 0.42-0.92, p = 0.001).
The incidence of grade ≥3 adverse events was 35% for targeted therapy and 40% for SoC.
The authors concluded that the ROME study demonstrated that a mutational-based treatment approach based on the MTB discussion of comprehensive genomic profiling results may significantly improve ORR and PFS compared to SoC in pretreated patients with metastatic solid tumours, particularly with immunotherapy.
Legal entity responsible for this study is Fondazione per la Medicina Personalizzata and the study was funded by Roche, Novartis, Pfizer, Bristol-Mayers-Squibb, Takeda Pharmaceutical Co., Incyte, Merck, Eli Lilly.
Reference
LBA7 – Botticelli A, Scagnoli S, Conte P, et al. The Rome Trial From Histology to Target: the Road to Personalize Targeted Therapy and Immunotherapy. Annals of Oncology 2024;35(Suppl 2):S1202.