Abstract

Background

Matched targeted therapies (MTT) given alone or in combination with systemic anti‐cancer therapies have delivered proven survival benefit for many people with newly diagnosed cancer. However, there is little evidence of their effectiveness in the recurrent or late‐stage setting. With this uncertainty, alongside the perception that late‐stage cancers are too genetically heterogenous or too mutationally diverse to benefit from matched targeted therapies, next‐generation sequencing (NGS) of tumours in people with refractory cancer remains a low priority. As a result, next‐generation sequencing testing of recurrent or late‐stage disease is discouraged. We lack evidence to support the utility of next generation sequencing in guiding matched targeted therapies in this setting.

Objectives

To evaluate the benefits and harms of matched targeted therapies in people with advanced cancers in randomised controlled trials.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, ClinicalTrials.gov, and the World Health Organisation International Clinical Trials Registry Platform (WHO‐ICTRP) search portal up to 30th October 2024. We also screened reference lists of included studies and also the publications that cited these studies.

Selection criteria

We included randomised controlled trials (RCTs) that had enroled participants with advanced/refractory solid or haematological cancers who had progressed through at least one line of standard anti‐cancer systemic therapy. To be eligible, all participants should have received matched targeted therapy based on next‐generation sequencing carried out on their tumour (tumour tissue, blood or bone marrow).

Data collection and analysis

We systematically searched medical databases (e.g. MEDLINE, Embase) and trial registers for randomised controlled trials (RCTs). Outcomes of interest were progression‐free survival (PFS), overall survival (OS), overall response rates (ORR), serious (grade 3 or 4) adverse events (AEs) and quality of life (QOL). We used a random‐effects model to pool outcomes across studies and compared predefined subgroups using interaction tests. Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment of certainty was used to evaluate the quality of evidence.

Main results

We identified a total of 37 studies, out of which 35 studies (including 9819 participants) were included in the meta‐analysis. All included studies compared a matched targeted therapy intervention to standard‐of‐care treatment, non‐matched targeted therapies or no treatment (best supportive care):

Matched targeted therapy versus standard‐of‐care treatment

Matched targeted therapy (MTT) compared with standard systematic therapy probably reduces the risk of disease progression by 34% (hazard ratio (HR) = 0.66, 95% confidence interval (CI) 0.59 to 0.74; 14 studies, 3848 participants; moderate‐certainty evidence). However, MTT might have little to no difference in risk of death (HR = 0.85, 95% CI 0.75 to 0.97; 14 studies, 3848 participants; low‐certainty evidence) and may increase overall response rates (low‐certainty evidence). There was no clear evidence of a difference in severe (grade 3/4) adverse events between matched targeted therapy and standard‐of‐care treatment (low‐certainty evidence). There was limited evidence of a difference in quality of life between groups (very low‐certainty of evidence).

Matched targeted therapy in combination with standard‐of‐care treatment versus standard‐of‐care treatment alone

Matched targeted therapy in combination with standard‐of‐care treatment compared with standard‐of‐care treatment alone probably reduces the risk of disease progression by 39% (HR = 0.61, 95% CI 0.53–0.70, 14 studies, 2,637 participants; moderate‐certainty evidence) and risk of death by 21% (HR = 0.79, 95% CI 0.70 to 0.89; 11 studies, 2575 participants, moderate‐certainty evidence). The combination of MTT and standard‐of‐care treatment may also increase overall response rates (low‐certainty evidence). There was limited evidence of a difference in the incidence of severe adverse events (very low‐certainty evidence) and quality of life between the groups (very low‐certainty of evidence).

Matched targeted therapy versus non‐matched targeted therapy

Matched targeted therapy compared with non‐matched targeted therapy probably reduces the risk of disease progression by 24% (HR = 0.76, 95% CI 0.64 to 0.89; 3 studies, 1568 participants; moderate‐certainty evidence) and may reduce the risk of death by 25% (HR = 0.75, 95% CI 0.65 to 0.86, 1307 participants; low‐certainty evidence). There was little to no effect on overall response rates between MTT and non‐MTT. There was no clear evidence of a difference in overall response rates (low‐certainty evidence) and severe adverse events between MTT and non‐MTT (low‐certainty evidence). None of the studies comparing MTT and non‐MTT reported quality of life.

Matched targeted therapy versus best supportive care

Matched targeted therapy compared with the best supportive care (BSC) i.e. no active treatment probably reduces the risk of disease progression by 63% (HR 0.37, 95% CI 0.28 to 0.50; 4 studies, 858 participants; moderate‐certainty evidence). There was no clear evidence of a difference in overall survival between groups (HR = 0.88, 95% CI 0.73 to 1.06, 3 studies, 783 participants; low‐certainty evidence). There was no clear evidence of a difference in overall response rates (very low‐certainty of evidence) and incidence of severe adverse events (very low‐certainty of evidence) between the groups. Quality of life was reported in a single study but did not provide composite scores.

Risk of bias

The overall risk of bias was judged low for eight studies, unclear for two studies, and the remaining 27 studies were high risk.

Authors' conclusions

Matched targeted therapies guided by next‐generation sequencing in people with advanced cancer prolongs the time before cancer progresses compared to standard therapies. However, there is limited evidence to suggest that it prolongs overall survival, improves the quality of life or increases adverse events. Importantly, this review supports equitable access to next‐generation sequencing technology for all people with advanced cancer and offers them the opportunity to access genotype‐matched targeted therapies.

Author(s)

Farasat Kazmi, Nipun Shrestha, Tik Fung Dave Liu, Thomas Foord, Philip Heesen, Stephen Booth, David Dodwell, Simon Lord, Kheng-Wei Yeoh, Sarah P Blagden

Abstract

Plain language summary

Does selecting targeted therapies based on genetic testing of an individual's cancer prolong their life or delay disease progression in people with advanced cancer?

Key messages

People with advanced cancers who received matched targeted therapies, either alone or in combination with standard treatments, experienced longer periods of disease control compared to those receiving standard treatments alone. However, the evidence on whether these therapies extend overall survival remains inconsistent. Further information is needed on the potential harms of matched targeted therapy and whether it improves the overall quality of life.

Early genetic testing using next‐generation sequencing is recommended for individuals with advanced cancers to help guide treatment with matched targeted therapies. While these therapies can be highly effective, it is crucial to carefully manage potential side effects and prioritise the individual’s overall wellbeing when making treatment decisions.

What do we already know?

Matched targeted therapies given alone or in combination with chemotherapy or hormonal therapies have delivered proven survival benefits for many people with newly diagnosed cancers. However, there is little evidence of their effectiveness in the recurrent or advanced setting. Therefore, next‐generation sequencing testing for recurrent or late stage disease is not routinely conducted in those people whose cancer has progressed through at least one line of standard anti‐cancer treatment.

What is next‐generation sequencing?

Next‐generation sequencing of cancer identifies specific mutations in the DNA of a person’s cancer cells. These mutations can give clinicians clues about why the cancer is growing and which treatments might work best. This helps choose "targeted therapies" designed to attack those specific mutations, making treatment more personalised and potentially more effective.

What did we want to find out?

The purpose of this review was to find out whether people with advanced cancers given matched targeted therapies based on mutations identified from next‐generation sequencing testing benefited these people more than those people who received non‐matched chemotherapy or hormonal therapy.

What did we do?

We searched for studies that investigated any matched targeted therapies compared to people who received standard chemotherapy or hormonal therapy or no treatment. Only adults older than 18 years were included in the review. We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes.

What did we find?

We found 37 studies with nearly 10,000 people with advanced cancers that had either received matched targeted therapies or standard anti‐cancer treatment or no treatment. We found the following:

1. Matched targeted therapies vs. standard treatment:

Matched targeted therapies probably delay cancer progression more effectively than standard‐of‐care treatments. However, it is still unclear whether targeted therapies also prolong the individual's life. They may also increase the overall response rate, but it was unclear whether the incidence of potential harms would increase with matched targeted therapy. There was not enough information about the benefits of matched targeted therapy on quality of life, as very few studies reported it.

2. Matched targeted therapies in combination with standard treatment vs standard treatment alone:

Combining matched targeted therapies with standard‐of‐care treatment probably delays the risk of cancer progression and also probably prolongs the individual's life. The combination may also increase the overall response rate. However, there was no clear evidence of the potential harm of combination treatment and its overall impact on quality of life.

3. Matched targeted therapies vs. non‐matched targeted therapy:

Matched targeted therapies probably have more benefits than targeted therapies not based on genetic matching in delaying cancer progression and prolonging the individual's life. However, there was no clear evidence of their impact on overall response rate and potential harms. No studies looked at whether the matched targeted therapy impacted the overall quality of life in this setting.

4. Matched targeted therapies vs. no active treatment (best supportive care):

Matched targeted therapies probably delay cancer progression compared to no active treatment. It is unclear if matched targeted therapies prolong the individual's life. There was limited evidence of the impact of matched targeted therapy on overall response rates, potential harms and its impact on overall quality of life.

Summary of findings

Matched targeted therapies can probably delay cancer progression, but there is some evidence to suggest that they help people live longer or improve their overall quality of life. Early access to genetic testing for people with advanced cancers could help identify treatment options and improve care. This review supports making genetic testing more available for people with advanced cancers.

What are the limitations of the evidence?

The certainty of evidence across the comparisons was moderate‐certainty for progression‐free survival, moderate to low‐certainty for overall survival and low to very low‐certainty for overall response rate, adverse events and quality of life, respectively. We have found limited evidence of the impact of matched targeted therapies on quality of life, as very few trials reported this outcome, which is an important outcome for determining the overall benefit of the drug.

How up‐to‐date is the evidence?
The review authors searched for studies that had been published up to October 2024.

Author(s)

Farasat Kazmi, Nipun Shrestha, Tik Fung Dave Liu, Thomas Foord, Philip Heesen, Stephen Booth, David Dodwell, Simon Lord, Kheng-Wei Yeoh, Sarah P Blagden

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

Based on data from all identified trials, matched targeted therapies using next‐generation sequencing testing probably prolong the time before cancer progresses compared to standard therapies. However, there is limited evidence to suggest that they prolong overall survival or improve the quality of life. There was no clear evidence of difference in severe adverse events with matched targeted therapies. Matched targeted therapies in combination with standard‐of‐care systemic therapies probably prolong the time before cancer progresses and also probably increase overall survival. Although there is some evidence that the benefit of this combination may come at the cost of increased severe adverse events, the evidence is very uncertain.

As the global cancer disparity and inequity continues to rise, considerations need to be given to the overall benefit and cost‐effectiveness of matched targeted therapies (Chen 2023). This is especially important as many targeted therapies are highly priced, sparking debates about their true value (Cherla 2020). Most importantly, we need to consider equitable access to next‐generation sequencing technology for all people with advanced cancer, providing them with the opportunity to access genotype‐matched targeted therapies as it has shown to delay cancer progression.

Implications for research 

In this review, we identified the importance of next‐generation sequence‐guided‐matched targeted therapies in patients with advanced cancers. In our subgroup analysis, we observed survival outcomes in favour of matched targeted therapies that had prior FDA/EMA approvals in other cancer sites, suggesting the importance of robust and validated biological data to identify potential actionable targets. It also further validates the use of the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) framework to rank actionable mutations and allocate resources accordingly.

A comprehensive grasp and classification of driver mutations across various cancer subtypes is essential. This understanding will offer crucial insights for the design of future biomarker‐based randomised control trials. Uncovering shared mutations associated with matched targeted therapies is pivotal for developing the next‐generation of targeted therapies, enabling the effective counteraction of resistance and unlocking the full potential of next‐generation sequencing (NGS).

Interestingly, only 14 (38%) of the 37 studies included across all comparisons reported quality of life as an outcome for our population of interest. Moreover, even studies that reported quality of life outcomes did not include data for all randomised participants. Future studies should, therefore, evaluate quality of life outcomes using validated scales alongside other endpoints, implement strategies for the optimal administration of quality of life questionnaires, and minimise missing data. It is important that this outcome is built into the study designs of future randomised controlled trials as a primary or secondary outcome. In this review, we found that matched‐targeted therapies in people in an advanced cancer setting can delay cancer progression but do not necessarily prolong life and therefore quality of life becomes paramount in this setting. In the future, individual participant data meta‐analysis should be performed on similar trials to gain a better understanding of adverse events with matched targeted therapies and, importantly, people that will benefit most from this treatment strategy.

We downgraded the certainty of evidence for most of the comparisons due to study limitations, i.e. not clearly reporting blinding of participants and personnel in the included studies. Future studies should aim to report how participants and personnel were prevented from knowing the allocated intervention during the study to improve the certainty of the evidence.

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