UK Stakeholder Perspectives on Surrogate Endpoints in Cancer, and the Potential for UK Real-World Datasets to Validate Their Use in Decision-Making

Figures & data

Table 1 Key Opinion Leader Views on Suitability of Selected Surrogate Endpoints

Endpoint	Summary	Relevance
		Adjuvant or Neoadjuvant Use	Advanced or Metastatic Disease
DFS	KOLs consider DFS as to be an appropriate efficacy endpoint for adjuvant/neoadjuvant therapies in indications with good prognosis and immature survival data Payers highlight that surrogate survival endpoints such as DFS will become more acceptable as newer products with improved efficacy are launched in earlier lines of therapy and correlation with long-term survival is established	Important relevant endpoint	Not important but relevant endpoint
MRD^a	KOLs expect MRD negativity to become a viable surrogate for early-line MM treatment in the absence of mature survival data, due to the correlation between MRD negativity and long-term survival. MRD is less relevant in advanced MM as it is more feasible to achieve mature PFS or OS data	Important relevant endpoint	Not important but relevant endpoint
pCR	pCR is relevant for indications that are treated with adjuvant and neoadjuvant immunotherapy or chemotherapy before resection. pCR allows measurement of biologic activity for solid tumors and can demonstrate correlation to excellent prognosis and long-term survival Payers agree with KOL expectations that pCR might become a key endpoint in the next 2–5 years for adjuvant/neoadjuvant therapies if correlation with long-term survival is established	Important relevant endpoint	Not important but relevant endpoint
DCR	DCR is likely to be an appropriate supporting endpoint to PFS in metastatic indications with good prognosis and immature OS data. KOLs consider DCR to be an appropriate evolving endpoint to measure progression of metastatic disease that is not being treated with curative intent and has progressed in spite of initial therapy	Not important but relevant endpoint	Important relevant endpoint
Relapse rate	Payers expect relapse rate to be an acceptable supporting endpoint for earlier lines of therapy but will require survival-related primary endpoints	Important relevant endpoint	Not important but relevant endpoint
Time to response	Payers do not expect to use time to response to assess new products during HTA evaluations as type of response and duration of response are considered more important than time to first response	Not important but relevant endpoint	Not important but relevant endpoint

Notes: Based on 10 interviews with 20 stakeholders for NSCLC, prostate cancer, bladder cancer, and colorectal cancer, and three interviews with four stakeholders for multiple myeloma. ^aRelevant only to MM.

Abbreviations: DCR, disease control rate; DFS, disease-free survival; HTA, health technology assessment; KOL, key opinion leader; MRD, minimal residual disease; MM, multiple myeloma; OS, overall survival; pCR, pathologic complete response; PFS, progression-free survival.

Table 2 Assessment Criteria for Data Sources

Category	Dimension	Definition
1. Access	Information governance	Relevant if researchers other than data controllers/existing named processors use the data for secondary (research) purposes.
2. Cancer cohort(s)	MM and LC	As defined by ICD10 codes C90 (MM) and C34 (LC)
3. Support	Specialist support	Data management team available with MM and LC specialist experience
4. Data documentation	Data model, data dictionary, and provenance	Documented data model, description of data items, and description of source
5. Technical quality	Data management plan and data completeness	Description of auditing processes and data profiling results available
6. Coverage	Time period, geography, and size	Follow-up period available for each patient record, area covered, and number of patients
7. Availability	Allowable uses, frequency, timeliness, tools, and environment	Description of license agreement, including allowable users, how often the data are refreshed, time between data application and access, statistical tools available in secure analytical environment, and description of location of data for analysis
8. Value	Linkages, enrichment, and costs	Identifiers to demonstrate ability to link to other datasets, ability to link to additional bespoke datasets, and data access fees

Table 3 Clinical Expert Discussion of Potential Surrogate Endpoints in MM: Transplant-Eligible Patients

Key Measure	Clinical Trial Endpoint	RWD and RWE Discussions	Currently Suitable as a Surrogate Endpoint?
Survival	OS	Improved survival means that trials in this cohort risk will be obsolete by the time of survival data readout. Subsequent lines of treatment are poorly reported in clinical trials. OS is not meaningful due to the potential length of survival and the impact of subsequent lines of treatment. RWD should be improved by measurement of disease/morbidity-related survival and possibly quality-adjusted and age-related relative survival. Patients’ perspectives on balancing HR-QoL with survival may differ.	No, but RW assessment of OS should be improved
Duration of response	PFS according to IMWG categories	PFS in first-line management offers greatest survival benefit, particularly the duration of first response versus early relapse. Numerical improvement in PFS is not relevant in an RW setting as it does not directly impact clinical care. Quantitative paraprotein/sFLC assessments that are routinely collected must be easier to obtain.	Yes
Depth of response/ kinetics of relapse	Response rate according to the International Uniform Response Criteria for Multiple Myeloma, including sCR, CR, VGPR, and PR.	Studies suggest that depth of response is less important than sustainability of VGPR. Biochemical laboratory RWD on relapse kinetics could be important, but easier access is required. Time without treatment is important to patients.	Yes
Residual tumor burden	MRD according to IMWG criteria.	MRD is currently measured at only one time point as standard. PET-CT MRD is expensive and not consistently available in the UK. Measurement of increasing depth of response or capture of relapse earlier would be ideal but change of clinical practice is not currently likely. The current frequency of assessments for MRD is unlikely to be applicable to the clinical setting due to patient and clinical burden and current need for invasive bone-marrow biopsies.	No
Negative impact of therapy	Safety assessments (ADRs) and treatment tolerance (dose reductions/ treatment discontinuation)	Includes renal impairment, neuropathy, immunodeficiency, infection, thrombosis, and hospitalizations. Assess ToT in first-line assessments to evaluate the impact of toxicities and consider timings of cycles, treatment delays, and dose reductions. Trial composite endpoints could include relevant assessments. Potential to also use recovery rates from HDT-ASCT treatment, including markers of frailty, but these assessments are not yet validated	Yes, including as part of a composite/multicomponent endpoint
HR-QoL (including impact of treatment and disease progression)	EQ-5D/EORTC-QLQ30 and PROs	Desired by patients, but EQ-5D not regularly used in clinical care. Other options might include wearable technologies (eg, fitness/mobility measures) and clinical measures (eg, hospitalization, length of stay, infection, and health-resource utilization). Access to GP records and natural language processing of clinical records could improve data capture.	Yes, for all patients, but lack of longitudinal HR-QoL data is a key issue

Abbreviations: ADR, adverse drug reaction; CR, complete response; EORTC, European Organization for Research and Treatment of Cancer; EQ-5D, EuroQoL 5D tool; HR-QoL, health-related quality of life; HDT-ASCT, high-dose chemotherapy followed by autologous stem cell transplantation; GP, general practitioner; IMWG, International Myeloma Working Group; MRD, minimal residual disease; OS, overall survival; PET-CT, positron emission tomography-computed tomography; PFS, progression-free survival; PR, partial response; PRO, patient-reported outcome. RW, real-world; RWD, real-world data; RWE, real-world evidence; sCR, stringent complete response; sFLC, serum free light chain; ToT, time on treatment; VGPR, very good partial response.

Table 4 Clinical Expert Discussion of Potential Surrogate Endpoints in Multiple Myeloma: Transplant-Ineligible Patients

Key Measure	Clinical Trial Endpoint	RWD and RWE Discussions	Currently Suitable as a Surrogate Endpoint?
Survival	OS	OS is often shortened by increased age and/or frailty. Comorbidities are likely, so cause of death is important to establish. Assessment of disease/morbidity-related survival is essential. Also consider quality-adjusted and age-related survival.	No, but RW assessment of OS should be improved
Duration of response	PFS according to IMWG categories	Less-pronounced correlation of OS in these patients is due to increased confounding factors. Appropriate adjustments (eg, age and/or frailty score) could help. Co-morbidities are also increasingly important. TTNT may be an option to explore. Composite trial endpoints could incorporate toxicities and treatment discontinuation. Consider including supportive therapy, such as transfusion, medications/analgesia, immunoglobulins, and antibiotics. Timing of referral to palliative care could be informative.	Yes
Depth of response/kinetics of relapse	Response rate according to International Uniform Response Criteria for Multiple Myeloma, including sCR, CR, VGPR, and PR.	Biochemical relapse kinetics could be important but easier access is required.	Yes
Residual tumor burden	MRD according to IMWG criteria	MRD is currently measured at only one time point as standard. PET-CT MRD is expensive and not consistently available in the UK. Measurement of increasing depth of response or capture of relapse earlier would be ideal but change of clinical practice is not currently likely. The current frequency of assessments for MRD is unlikely to be applicable to the clinical setting due to patient and clinical burden and current need for invasive bone-marrow biopsies.	No
Negative impact of therapy	Safety assessments (ADRs) and treatment tolerance (dose reductions/ treatment discontinuation)	Includes renal impairment, neuropathy, immunodeficiency, infection, thrombosis, and hospitalizations. Assess ToT in first-line assessments to evaluate impact of toxicities and consider timings of cycles, treatment delays, and dose reductions. Trial composite endpoints could include relevant assessments. Potential to also use recovery rates from HDT-ASCT treatment, including markers of frailty, but these assessments are not yet validated	Yes, including as part of a composite/multicomponent tool
HR-QoL (including impact of treatment and disease progression)	EQ-5D/EORTC-QLQ30	Desired by patients, but EQ-5D not regularly used in clinical care. Other options might include wearable technologies (eg, fitness/mobility measures), clinical measures (eg, hospitalization, length of stay, infection, and health-resource utilization). Access to GP records and natural language processing of clinical records could improve data capture.	Yes, for all patients

Abbreviations: ADR, adverse drug reaction; CR, complete response; EORTC, European Organization for Research and Treatment of Cancer; EQ-5D, EuroQoL 5D tool; GP, general practitioner; HDT-ASCT, High-dose chemotherapy followed by autologous stem-cell transplantation; HR-QoL, health-related quality of life; IMWG, International Myeloma Working Group; MRD, minimal residual disease; OS, overall survival; PET-CT, positron emission tomography-computed tomography; PFS, progression-free survival; PR, partial response; RW, real-world; RWD, real-world data; RWE, real-world evidence; sCR, stringent complete response; ToT, time on treatment; TTNT, time to next treatment; VGPR, very good partial response.

Table 5 Clinical Expert Discussion of Potential Surrogate Endpoints in Multiple Myeloma: Relapsing or Refractory Patients

Key Measure	Clinical Trial Endpoint	RWD and RWE Discussions	Currently Suitable as a Surrogate Endpoint?
Survival	OS	OS is usually shorter in this population and more likely to be the most meaningful outcome measure, if readout of survivorship is optimized. The justification for other endpoints, particularly in relapsing/refractory patients, is less compelling.	No, but RW assessment of OS should be improved
Duration of response	PFS2	Moderate to strong correlation with OS is possible but not proven. Potentially too many confounders in this population to be meaningful, but the relapsing patients should still be included in a TTNT assessment.	Yes, but only for relapsing patients
Kinetics of relapse	Response rate according to International Uniform Response Criteria for Multiple Myeloma, including sCR, CR, VGPR, and PR.	Biochemical laboratory RWD on relapse kinetics could be important but easier access is required.	Yes, but only for relapsing patients
Negative impact of therapy	Safety assessments (ADRs) and treatment tolerance (dose reductions/ treatment discontinuation)	Includes renal impairment, neuropathy, immunodeficiency, infection, thrombosis, and hospitalizations. Assess ToT in first-line assessments to evaluate the impact of toxicities and consider timings of cycles, treatment delays, and dose reductions. Trial composite endpoints could include relevant assessments. Potential to also use recovery rates from HDT-ASCT treatment, including markers of frailty, but these assessments are not yet validated.	Yes, including as part of a composite/ multicomponent tool
HR-QoL (including impact of treatment and disease progression)	EQ-5D/EORTC-QLQ30	Desired by patients, but EQ-5D not regularly used in clinical care. Other options might include wearable technologies (eg, fitness/mobility measures), clinical measures (eg, hospitalization, length of stay, infection, and health-resource utilization). Access to GP records and natural language processing of clinical records could improve data capture.	Yes, for all patients

Abbreviations: ADR, adverse drug reaction; CR, complete response; EORTC, European Organization for Research and Treatment of Cancer; EQ-5D, EuroQoL 5D tool; GP, general practitioner; HR-QoL, health-related quality of life; OS, overall survival; PFS2, time from randomization to progression on second-line therapy; PR, partial response; RW, real-world; RWD, real-world data; RWE, real-world evidence; sCR, stringent complete response; TTNT, time to next treatment; ToT, time on treatment; VGPR, very good partial response.

Table 6 Discussion of Additional Potential Surrogate Endpoints in MM Based on RWD and RWE

Key Measure	RWD and RWE Discussion	Currently Suitable as a Surrogate Endpoint?
Markers of immunological fitness	Considered important, potentially as a component of other confounding factors.	Maybe, as part of assessment of previous treatment
Quantitative assessments of physical fitness	Important HR-QoL parameter that could be considered (eg, what are you able to do whilst on treatment?).	Maybe, as part of assessment of HR-QoL
Biochemical identification of frail patients (eg, MRP)	Risk-adapted disease management is becoming increasingly important. MRP could offer a biochemical indicator but has not been validated as an outcome measure.	No
Functional consequences of disease progression (renal/anemia)	May be a meaningful assessment as part of a composite assessment in combination with relapse rate. Biochemical assessment of organ damage was proposed, including renal function, hemoglobin, calcium, and bone disease (eg, skeletal-related events)	Yes, as part of biochemical assessment of relapse kinetics and disease progression (as a composite or multicomponent endpoint)

Abbreviations: HR-QoL, health-related quality of life; MRP, UK Myeloma Research Alliance Risk Profile. RWD, real-world data; RWE, real-world evidence.

Table 7 Clinical Expert Discussion of Potential Surrogate Endpoints in Lung Cancer: Stage I and II Disease

Key Measure	Clinical Trial Endpoint	RWD and RWE Discussions	Currently Suitable as a Surrogate Endpoint?
Survival	OS	OS is least meaningful in early-stage disease due to curative intent of treatment and potentially long survival. It is also confounded by multiple factors in RWD, many of which cannot be effectively measured. Measurement of disease/morbidity-related survival is essential. Recurrence-free survival can be very difficult to determine from RWD on mortality. Quality-adjusted survival and age-related relative survival should also be considered. Mortality rates and mortality per person-years (age standardized) could be informative. Patients want to know the likelihood of survival by time and/or the probability of death or disease status.	No, but RW assessment of OS should be improved
Recurrence of disease/duration of response	DFS (increasingly accepted by regulators)	Important to determine effective personalized adjuvant therapies; must be contextualized with data on patients’ characteristics and comorbidities. Frequency of scans to detect disease recurrence needs to be improved. Need to identify appropriate correlation factor to OS (eg, 2 years or 5 years).	Yes, so long as it shows any magnitude of change/ differentiation
Pathological assessments	Pathological stage/prognosis	TNM-PS staging remains the standard. Combined endpoints could be informative for assessing predictive potential of key assessments (eg, vascular invasion, volume doubling) but are still not clearly defined. Reporting and standardization of data recording for other factors could be improved.	No
Residual disease assessments	MRD negativity based on assessments of ctDNA	Interesting preliminary data on the utility of ctDNA assessments but is still in very early stages of validation and potential clinical adoption. ctDNA has the clear potential to be much more sensitive at detecting the presence of disease than a scan.	No, but should undergo further exploration
HR-QoL	EQ-5D/EORTC-QLQ30	The link between DFS and long-term HR-QoL is important for early-stage adjuvant treatments. Could consider correlating DFS/PFS to HR-QoL, particularly in early disease. PROs are not captured sufficiently to understand true impact on HR-QoL. Classification by “health states” and assessment in studies might be useful as a surrogate endpoint for HR-QoL.	Yes, for all patients
Other prognostic factors	Confounders often “selected out” by trial inclusion and exclusion criteria	It may be difficult to subcategorize prognostic factors beyond TNM-PS and even in composite measures this indicator appears to outweigh other factors. Early detection of tumors is a known prognostic factor and potentially indicates a more indolent tumor with better survival outcomes. Achieving earlier diagnosis is important (eg, through more effective screening) and tumor aggressiveness should be included in the prognostic assessment. Type of surgery/radiotherapy are also known as prognostic factors for survival. PS is favored over frailty assessments. Collection methods need to be simple but ensure that the nuances may be captured.	It was suggested that baseline characteristics and other key indicators and indolence/ aggressiveness of the tumor could be used to place surrogate endpoints such as DFS in context

Abbreviations: ctDNA, circulating tumor DNA; DFS, disease-free survival; EORTC, European Organization for Research and Treatment of Cancer; EQ-5D, EuroQoL 5D tool; HR-QoL, health-related quality of life; MRD, minimal residual disease; OS, overall survival; PRO, patient-reported outcome; PS, performance status; RW, real-world; RWD, real-world data; RWE, real-world evidence; TNM-PS, tumor node metastasis status and performance status.

Table 8 Clinical Expert Discussion of Potential Surrogate Endpoints in Lung Cancer: Stage III Disease

Key Measure	Clinical Trial Endpoint	RWD and RWE Discussions	Currently Suitable as a Surrogate Endpoint?
Survival	OS	OS is least meaningful as curative intent remains in this population. It is also confounded by multiple factors in RWD, many of which cannot be effectively measured.	Not a surrogate endpoint, but RW assessment of OS should be improved
Recurrence of disease	DFS	Important to determine effective personalized adjuvant therapies; must be contextualized with data on patients’ characteristics and comorbidities, but morphological changes due to the treatments can make the imaging difficult to interpret. Frequency of scans to detect disease recurrence needs to be improved. Need to identify appropriate correlation factor to OS (eg, 2 years or 5 years). Understanding of wider imaging modalities needs to be improved (eg, PET standardized uptake values). Improved data on proportion of patients responding to treatment/extent of response would be beneficial.	No
Pathological response	Pathological response	Whether major versus complete pathological response is most appropriate is unclear, and assessment approaches differ. Pathological response assessments take a long and require specific training, which affects applicability in clinical practice. What value data collected in a clinical trial setting and used in the regulatory approval process offer to the clinical setting is unclear. Pathological assessment measures response only in resected tumors but not residual tumor or micrometastatic disease	No
Residual disease assessments	MRD negativity based on assessments of ctDNA	Interesting preliminary data on the utility of ctDNA assessments but is still in very early stages of validation and potential clinical adoption. ctDNA has the clear potential to be much more sensitive at detecting the presence of disease than a scan.	Should undergo further exploration
Negative impact of therapy	Surgical/ radiotherapy complications, ADRs, and treatment tolerance	Composite RW surrogates that offer a more comprehensive evaluation of the benefit and adverse outcomes of treatments could provide clinical value but will be challenging to undertake.	Likely too complicated to take forward
Overall QoL (including impact of treatment and disease progression)	EQ-5D/EORTC-QLQ30	Lack of longitudinal data is a key issue. If measured in trials, data are generally not reported or used. QALYs might offer a direct assessment pathway but require longer-term measurements of HR-QoL. Collection methods need to be simple but ensure that the nuances may be captured. How regulators value HR-QoL needs clarification. New technologies, such as smart phone applications and wearables, could be important for capture of QoL data. Access to GP records may be useful and natural language processing of clinical records could be considered to improve capture of data.	Yes, for all patients

Abbreviations: ADR, adverse drug reaction; ctDNA, circulating tumor DNA; DFS, disease-free survival; EORTC, European Organization for Research and Treatment of Cancer; EQ-5D, EuroQoL 5D tool; GP, general practitioner; HR-QoL, health-related quality of life; QoL, quality of life; MRD, minimal residual disease; OS, overall survival; PET, positron emission tomography; PS, performance status; QALY, quality-adjusted life-years. RW, real-world; RWD, real-world data; RWE, real-world evidence; TNM-PS, tumor node metastasis status and performance status.

Box 1 Surrogate Endpoint Recommendations for Multiple Myeloma

The following surrogate endpoints were suggested by the clinical experts for further assessment: In patients receiving first-line treatment (transplant eligible and ineligible) or experiencing an initial relapse from therapy: Time to next treatment as an indicator of disease progression Biochemical relapse kinetics by rate of rise of paraprotein or serum-free light chain, potentially alongside incorporation of biochemical indicators of disease progression/organ damage as a composite assessment In relapsed patients: 3. Additional measures to evaluate how well the patient tolerated/responded to previous treatment, eg, as part of a composite endpoint In all patients: 4. Improved collection, evaluation, and use of longitudinal health-related quality of life (in the absence of overall quality-of-life surrogate endpoints) at all stages of treatment. In the absence of patient-reported health-related quality of life, potential proxies for real-world data could be hospitalization, infection, and health-resource utilization.

Box 2 Surrogate Endpoint Recommendations for Lung Cancer

In early-stage disease (stage I and II): Disease-free survival through either the capture of i) a documented recurrence (scan or positive pathology); ii) a measure of the disease-free period (eg, treatment change or initiation of a new therapy), or iii) death. (May also include assessment of patient notes in electronic health records.) In all patients: 2. Improved collection, evaluation, and use of longitudinal health-related quality of life data (in the absence of overall quality-of-life surrogate endpoints) for all patients, but particularly during end-stage disease. In the absence of patient-reported health-related quality of life, potential proxies for real-world data could be health needs assessments, number of drug therapies, and frailty indices.