3O - Are targeted therapies effective in the relapsed or metastatic cancer setting? A Cochrane meta-analysis

Background

Although molecularly-targeted therapies (MTT) given alone or in combination with chemotherapy have delivered proven survival benefit for many newly diagnosed cancers, there is little evidence of their efficacy in recurrent or late-stage settings. With this uncertainty, alongside a perception that late-stage cancers are too genetically heterogenous or too mutationally diverse to benefit from MTTs, next generation sequencing (NGS) of heavily-pretreated patients remains a low priority. Indeed, outside rare cancer contexts or for specific clinical trial screening, NGS testing of recurrent or late stage disease is discouraged (Colomer et al, 2023). To systematically explore this question, we conducted a Cochrane meta-analysis to explore the effectiveness and safety of MTTs in relapsed or metastatic cancers refractory to standard therapies.

Methods

We searched medical databases (e.g. Medline, Embase) and trial registers for RCTs and non-RCTs. Outcomes of interest were progression-free survival (PFS), overall survival (OS), overall response rates (ORR) and serious (Grade 3 or 4) adverse events (AEs). We used random effects modelling to pool outcomes across studies and compared pre-defined subgroups using interaction tests. GRADE assessment of certainty was used to evaluate the quality of evidence.

Results

Of 9784 identified records, 23 were eligible for inclusion (16 RCTs and 7 non-RCTs; n=5466 patients). Compared to standard therapy, MTTs displayed significant improvement in PFS (HR 0.70, 95% CI 0.59–0.84), OS (HR 0.78, 95% CI 0.67–0.91), and ORR (OR 2.90, 95% CI 1.66–5.05). MTT in combination with standard therapy also significantly improved PFS (HR 0.64, 95% CI 0.50–0.81), OS (HR 0.72, 95% CI 0.57–0.92), and ORR (OR 2.71, 95% CI 1.58–4.65) compared to standard therapy alone. However, MTT had significantly increased risk of G3/4 AEs when compared to standard of care treatment (RR 2.14, 95% CI 1.81–2.53) but this did not impact patient QoL.

Conclusions

Here, we provide the first level 1 evidence that matched targeted therapies confer both PFS and OS benefit to heavily pre-treated patients with advanced/metastatic cancers. Our findings support the routine use of NGS and targeted-treatment matching, even in the late stage cancer setting.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

Cochrane.

Funding

Has not received any funding.

Disclosure

S. Lord: Financial Interests, Personal, Advisory Board: Sanofi, Rejuversen; Financial Interests, Personal, Invited Speaker: Sanofi, Prosigna, Eisai, Roche, Pfizer, Novartis; Financial Interests, Personal, Ownership Interest, Co-founder of company: Mitox Therapeutics; Financial Interests, Institutional, Invited Speaker: Boehringer Ingelheim, PIQUR Therapeutics, AstraZeneca, Merck KGaA, Carrick Therapeutics, Sanofi, Synthon, Roche, BioInvent International, RS Oncology; Financial Interests, Institutional, Research Grant: Pathios Therapeutics; Non-Financial Interests, Personal, Advisory Role: Carrick Therapeutics. All other authors have declared no conflicts of interest.