Mutational-based treatment approach may significantly improve outcomes in pretreated patients with metastatic solid tumours
Dr Andrea Botticelli - Sapienza Università di Roma, Rome, Italy
We are going to present at ESMO 2024 the final results of the ROME trial. The ROME trial is a phase II trial with the aim to demonstrate if a diagnostic approach could be superior to standard of care. The ROME trial is a phase II multicentre, multi-basket trial in which patients affected by solid tumours, regardless of histology, who had received at least one line of previous therapy but no more than two lines of previous therapy were screened. For each patient we performed comprehensive genomic profiling, both on tissue and liquid biopsy, and once molecular alterations that could be targeted with a drug available in the ROME trial were identified, the clinical case was reviewed and discussed in the molecular tumour board. Then the molecular tumour board decided whether to enrol the patient and proceed with randomisation or to consider patient screening failure.
All patients enrolled were randomised to receive 1:1 standard of care proposed by the investigators, or targeted therapy according to the mutational profile. Also a crossover phase was planned. The primary endpoint of the ROME trial was objective response rate and the secondary endpoints were progression free survival, overall survival, time to treatment failure, time to next treatment and safety profile.
We have also several exploratory endpoints such as the PFS in the ITT arm versus standard of care in a homogeneous subgroup of patients.
The ROME trial involved forty referral oncological centres in Italy and we had 26 different drugs that could be administered, both in monotherapy or in a combination strategy. From November 2020 to August 2023 1,794 patients were screened and of them 897 patients presented with relevant alterations, so almost 55% of patients. These patients were discussed in the molecular tumour board and after 127 weekly molecular tumour boards 400 patients were enrolled. In the ITT population the most frequent alterations reported were high tumour mutational burden in 34% of patients, alteration of the PIK3CA pathway in 25% of patients, the alteration of ERBB2, either amplification and mutation, in 14% of patients, in 8% of patients alterations of FGFR and 4% of patients MSI. All patients with MSI presented also high tumour mutational burden. The most frequent drugs proposed by the molecular tumour board were ipilimumab, nivolumab, pemigatinib, TDM-1 and ipatasertib.
The primary endpoint of the ROME trial was objective response rate and the ROME trial met its primary endpoint. Indeed, the objective response rate was 17% in the ITT arm versus 9.5% in standard of care. In 2.5% of patients in the ITT arm we achieved a complete response.
Targeted therapy demonstrated also an improvement in progression free survival with a PFS rate at one year of 22 months versus 7 months in the standard of care. Unfortunately, targeted therapy didn’t demonstrate an improvement in overall survival but it’s important to consider that crossover was planned and 52% of patients in standard of care were treated with targeted therapy in the crossover phase.
The steering committee decided also to present at ESMO the data of patients with high tumour mutational burden. We defined high tumour mutational burden with a threshold of 10 mutations per megabase, either on tissue or on liquid biopsy. We distinguished these patients as patients with MSI and MSS. All these patients were treated with immunotherapy as a targeted therapy and the benefit in terms of progression free survival was seen both in MSI patients and in MSS patients with a PFS rate in MSI targeted therapy of 57% at one year versus zero in the standard of care. While in the MSS subgroup of patients the PFS rate was 32% in targeted therapy versus 6% in the standard of care.
In conclusion, in the metastatic patients targeted therapy driven by comprehensive genomic profiling and molecular tumour board activity could improve progression free survival and objective response rate with a long-term benefit in terms of progression free survival. Unfortunately, we didn’t demonstrate an improvement in overall survival, even though crossover was planned and 52% of patients in standard of care were treated with a targeted therapy in the crossover phase.
The safety profile of targeted therapy is similar in terms of severe toxicity compared with standard of care, even though the toxicity profiles were, however, different because we had 30 different drugs in standard of care in the ITT arm. It’s really clear that in this novel landscape of mutational approach, the molecular tumour board is really playing a crucial role to decide the right moment to prescribe comprehensive genomic profiling for patients to really understand the mutational report to choose the treatment and to share their knowledge of clinical trials and to allow access for patients to the novel treatment.
The ROME trial fits in the novel landscape of mutational approaches in which it’s clear that we need to really understand the novel rules to manage the patient treatment and the patient journey. In this novel role it's really crucial to understand the role of the molecular tumour board and how to apply in the right way the knowledge about the comprehensive genomic profile to define the right therapy in the right choice in the right time for the right patient.
