Regulatory and valuation challenges of immune checkpoint inhibitors in lung cancer

Advances in innovative drug development translated into tangible improvements in clinical outcomes for patients with non-small cell lung cancer (NSCLC). Immunotherapy, specifically immune checkpoint inhibitors (ICIs), has transformed the standard of care for NSCLC patients. Although ICIs have brought meaningful opportunities in NSCLC care and transformed the treatment landscape, their regulatory decisions and economic value assessments pose important challenges. In this research, regulatory and valuation challenges of ICIs in NSCLC were explored to help support the future use of ICIs in health systems

Analysis of patient reported outcomes included in the registrational clinical trials of nivolumab for advanced non-small cell lung cancer

In the era of value-based oncology care, stakeholders are increasingly using patient reported outcomes (PROs) to guide clinical and regulatory decisions. PROs are also included in health technology assessments to guide patient access, drug reimbursement and pricing. We reviewed PROs collected in the United States Food and Drug Administration approved indications of nivolumab in advanced NSCLC. We analyzed the PRO data reported in the CheckMate 9LA (NCT03215706), CheckMate 227 (NCT02477826), CheckMate 057 (NCT01673867), and CheckMate 017 (NCT01642004) registrational clinical trials, and concluded that nivolumab alleviated symptom burden and improved health status of patients in this setting. However, inability of the included PRO instruments to measure immune-related adverse events, differences in the timing of PRO evaluation between treatment groups, incomplete patient participation at all time points, limited patient participation in the later time points, and interpretation of the longitudinal data are key challenges that impede accurate analysis and validation of PROs.</p

Cost-effectiveness analysis of the first-line EGFR-TKIs in patients with non-small cell lung cancer harbouring EGFR mutations

Objectives: To compare the cost-effectiveness of first-line gefitinib, erlotinib, afatinib, and osimertinib in patients with non-small cell lung cancer (NSCLC) harbouring epidermal growth factor receptor (EGFR) mutations. Methods: A systematic review and network meta-analysis (NMA) were conducted to compare the relative efficacy of gefitinib, erlotinib, afatinib, and osimertinib in EGFR-mutated NSCLC. To assess the cost-effectiveness of these treatments, a Markov model was developed from Dutch societal perspective. The model was based on the clinical studies included in the NMA. Incremental costs per life-year (LY) and per quality-adjusted life-year (QALY) gained were estimated. Deterministic and probabilistic sensitivity analyses (PSA) were conducted. Results: Total discounted per patient costs for gefitinib, erlotinib, afatinib, and osimertinib were €65,889, €64,035, €69,418, and €131,997, and mean QALYs were 1.36, 1.39, 1.52, and 2.01 per patient, respectively. Erlotinib dominated gefitinib. Afatinib versus erlotinib yielded incremental costs of €27,058/LY and €41,504/QALY gained. Osimertinib resulted in €91,726/LY and €128,343/QALY gained compared to afatinib. PSA showed that gefitinib, erlotinib, afatinib, and osimertinib had 13%, 19%, 43%, and 26% probability to be cost-effective at a threshold of €80,000/QALY. A price reduction of osimertinib of 30% is required for osimertinib to be cost-effective at a threshold of €80,000/QALY. Conclusions: Osimertinib has a better effectiveness compared to all other TKIs. However, at a Dutch threshold of €80,000/QALY, osimertinib appears not to be cost-effective

Cost-effectiveness analysis of the first-line EGFR-TKIs in patients with non-small cell lung cancer harbouring EGFR mutations

Objectives: To compare the cost-effectiveness of first-line gefitinib, erlotinib, afatinib, and osimertinib in patients with non-small cell lung cancer (NSCLC) harbouring epidermal growth factor receptor (EGFR) mutations. Methods: A systematic review and network meta-analysis (NMA) were conducted to compare the relative efficacy of gefitinib, erlotinib, afatinib, and osimertinib in EGFR-mutated NSCLC. To assess the cost-effectiveness of these treatments, a Markov model was developed from Dutch societal perspective. The model was based on the clinical studies included in the NMA. Incremental costs per life-year (LY) and per quality-adjusted life-year (QALY) gained were estimated. Deterministic and probabilistic sensitivity analyses (PSA) were conducted. Results: Total discounted per patient costs for gefitinib, erlotinib, afatinib, and osimertinib were €65,889, €64,035, €69,418, and €131,997, and mean QALYs were 1.36, 1.39, 1.52, and 2.01 per patient, respectively. Erlotinib dominated gefitinib. Afatinib versus erlotinib yielded incremental costs of €27,058/LY and €41,504/QALY gained. Osimertinib resulted in €91,726/LY and €128,343/QALY gained compared to afatinib. PSA showed that gefitinib, erlotinib, afatinib, and osimertinib had 13%, 19%, 43%, and 26% probability to be cost-effective at a threshold of €80,000/QALY. A price reduction of osimertinib of 30% is required for osimertinib to be cost-effective at a threshold of €80,000/QALY. Conclusions: Osimertinib has a better effectiveness compared to all other TKIs. However, at a Dutch threshold of €80,000/QALY, osimertinib appears not to be cost-effective

Faecal immunochemical tests (FIT) can help to rule out colorectal cancer in patients presenting in primary care with lower abdominal symptoms:a systematic review conducted to inform new NICE DG30 diagnostic guidance

__Background:__ This study has attempted to assess the effectiveness of quantitative faecal immunochemical tests (FIT) for triage of people presenting with lower abdominal symptoms, where a referral to secondary care for investigation of suspected colorectal cancer (CRC) is being considered, particularly when the 2-week criteria are not met. __Methods:__ We conducted a systematic review following published guidelines for systematic reviews of diagnostic tests. Twenty-one resources were searched up until March 2016. Summary estimates were calculated using a bivariate model or a random-effects logistic regression model. __Results:__ Nine studies are included in this review. One additional study, included in our systematic review, was provided as 'academic in confidence' and cannot be described herein. When FIT was based on a single faecal sample and a cut-off of 10 μg Hb/g faeces, sensitivity estimates indicated that a negative result using either the OC-Sensor or HM-JACKarc may be adequate to rule out nearly all CRC; the summary estimate of sensitivity for the OC-Sensor was 92.1%, based on four studies, and the only study of HM-JACKarc to assess the 10 μg Hb/g faeces cut-off reported a sensitivity of 100%. The corresponding specificity estimates were 85.8% (95% CI 78.3-91.0%) and 76.6%, respectively. When the diagnostic criterion was changed to include lower grades of neoplasia, i.e. the target condition included higher risk adenoma (HRA) as well as CRC, the rule-out performance of both FIT assays was reduced. __Conclusions:__ There is evidence to suggest that triage using FIT at a cut-off around 10 μg Hb/g faeces has the potential to correctly rule out CRC and avoid colonoscopy in 75-80% of symptomatic patients. Systematic review registration: PROSPERO 4201603772

Attribution of value for combination immune checkpoint inhibitors in non-small cell lung cancer

Immunotherapy represents a significant breakthrough in the treatment of cancer, including non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors (ICIs) are used in combination with other treatments to provide clinically meaningful outcomes for NSCLC patients. However, there are distinct mechanisms of action that an ICI may provide such clinically meaningful benefits. We focused on the valuation of ICIs when used in combination with existing treatments for NSCLC, by addressing the following questions: (1) do combination ICIs improve clinical outcomes due to independent, rather than synergistic or additive drug action; and (2) how should we attribute value to the constituent parts of combination ICIs? To address these questions, we reviewed the United States Food and Drug Administration (FDA) drug database and Clinicaltrials.gov from January 1, 2012, until June 1, 2022, to identify approved indications of combination ICIs in NSCLC. For valuation methods, a separate search was conducted in PubMed, health technology assessment databases, and grey literature to identify published value assessment or attribution methods, specifically in the context of combination (cancer) treatments. As of June 1, 2022, the FDA approved eight combination ICI indications for NSCLC. The underlying mechanisms for the improved clinical benefits of these ICI therapies are not well studied. The superiority of combination ICI therapies compared to monotherapy in multiple indications does not indicate whether synergy or additivity is involved, or necessary. Policy statement: We encourage further research on the development of value attribution framework methods for combination therapies to quantify their added health benefits and economic value in the future. Given the valuation challenges of combination ICIs, their mechanism of action poses significant uncertainty and requires further clinical investigation to address whether synergy or additivity is existent

Attribution of value for combination immune checkpoint inhibitors in non-small cell lung cancer

Immunotherapy represents a significant breakthrough in the treatment of cancer, including non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors (ICIs) are used in combination with other treatments to provide clinically meaningful outcomes for NSCLC patients. However, there are distinct mechanisms of action that an ICI may provide such clinically meaningful benefits. We focused on the valuation of ICIs when used in combination with existing treatments for NSCLC, by addressing the following questions: (1) do combination ICIs improve clinical outcomes due to independent, rather than synergistic or additive drug action; and (2) how should we attribute value to the constituent parts of combination ICIs? To address these questions, we reviewed the United States Food and Drug Administration (FDA) drug database and Clinicaltrials.gov from January 1, 2012, until June 1, 2022, to identify approved indications of combination ICIs in NSCLC. For valuation methods, a separate search was conducted in PubMed, health technology assessment databases, and grey literature to identify published value assessment or attribution methods, specifically in the context of combination (cancer) treatments. As of June 1, 2022, the FDA approved eight combination ICI indications for NSCLC. The underlying mechanisms for the improved clinical benefits of these ICI therapies are not well studied. The superiority of combination ICI therapies compared to monotherapy in multiple indications does not indicate whether synergy or additivity is involved, or necessary. Policy statement: We encourage further research on the development of value attribution framework methods for combination therapies to quantify their added health benefits and economic value in the future. Given the valuation challenges of combination ICIs, their mechanism of action poses significant uncertainty and requires further clinical investigation to address whether synergy or additivity is existent

Cost-effectiveness of first line nivolumab-ipilimumab combination therapy for advanced non-small cell lung cancer: A systematic review and methodological quality assessment

To assess the methodological quality of cost-effectiveness analyses (CEA) of nivolumab in combination with ipilimumab, we conducted a systematic literature review in the first-line treatment of patients with recurrent or metastatic non-small cell lung cancer (NSCLC), whose tumors express programmed death ligand-1, with no epidermal growth factor receptor or anaplastic lymphoma kinase genomic tumor aberrations. PubMed, Embase, and the Cost-Effectiveness Analysis Registry were searched, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The methodological quality of the included studies was assessed by the Philips checklist and the Consensus Health Economic Criteria (CHEC) checklist. 171 records were identified. Seven studies met the inclusion criteria. Cost-effectiveness analyses differed substantially due to the applied modeling methods, sources of costs, health state utilities, and key assumptions. Quality assessment of the included studies highlighted shortcomings in data identification, uncertainty assessment, and methods transparency. Our systematic review and methodology assessment revealed that the methods of estimation of long-term outcomes, quantification of health state utility values, estimation of drug costs, the accuracy of data sources, and their credibility have important implications on the cost-effectiveness outcomes. None of the included studies fulfilled all of the criteria reported in the Philips and the CHEC checklists. To compound the economic consequences presented in these limited number of CEAs, ipilimumab's drug action as a combination therapy poses significant uncertainty. We encourage further research to address the economic consequences of these combination agents in future CEAs and the clinical uncertainties of ipilimumab for NSCLC in future trials